Nanoparticulate fibrate formulations

ABSTRACT

The present invention is directed to fibrate compositions having improved pharmacokinetic profiles and reduced fed/fasted variability. The fibrate particles of the composition have an effective average particle size of less than about 2000 nm.

FIELD OF THE INVENTION

The present invention relates to a nanoparticulate compositioncomprising a fibrate, preferably fenofibrate or a salt thereof. Thenanoparticulate fibrate, preferably fenofibrate, particles have aneffective average particle size of less than about 2000 nm.

BACKGROUND OF THE INVENTION

A. Background Regarding Nanoparticulate Compositions

Nanoparticulate compositions, first described in U.S. Pat. No. 5,145,684(“the '684 patent”), are particles consisting of a poorly solubletherapeutic or diagnostic agent having adsorbed onto the surface thereofa non-crosslinked surface stabilizer. The '684 patent does not describenanoparticulate compositions of a fibrate.

Methods of making nanoparticulate compositions are described in, forexample, U.S. Pat. Nos. 5,518,187 and 5,862,999, both for “Method ofGrinding Pharmaceutical Substances;” U.S. Pat. No. 5,718,388, for“Continuous Method of Grinding Pharmaceutical Substances;” and U.S. Pat.No. 5,510,118 for “Process of Preparing Therapeutic CompositionsContaining Nanoparticles.”

Nanoparticulate compositions are also described, for example, in U.S.Pat. No. 5,298,262 for “Use of Ionic Cloud Point Modifiers to PreventParticle Aggregation During Sterilization;” U.S. Pat. No. 5,302,401 for“Method to Reduce Particle Size Growth During Lyophilization;” U.S. Pat.No. 5,318,767 for “X-Ray Contrast Compositions Useful in MedicalImaging;” U.S. Pat. No. 5,326,552 for “Novel Formulation ForNanoparticulate X-Ray Blood Pool Contrast Agents Using High MolecularWeight Non-ionic Surfactants;” U.S. Pat. No. 5,328,404 for “Method ofX-Ray Imaging Using Iodinated Aromatic Propanedioates;” U.S. Pat. No.5,336,507 for “Use of Charged Phospholipids to Reduce NanoparticleAggregation;” U.S. Pat. No. 5,340,564 for “Formulations Comprising Olin10-G to Prevent Particle Aggregation and Increase Stability;” U.S. Pat.No. 5,346,702 for “Use of Non-Ionic Cloud Point Modifiers to MinimizeNanoparticulate Aggregation During Sterilization;” U.S. Pat. No.5,349,957 for Preparation and Magnetic Properties of Very SmallMagnetic-Dextran Particles;” U.S. Pat. No. 5,352,459 for “Use ofPurified Surface Modifiers to Prevent Particle Aggregation DuringSterilization;” U.S. Pat. Nos. 5,399,363 and 5,494,683, both for“Surface Modified Anticancer Nanoparticles;” U.S. Pat. No. 5,401,492 for“Water Insoluble Non-Magnetic Manganese Particles as Magnetic ResonanceEnhancement Agents;” U.S. Pat. No. 5,429,824 for “Use of Tyloxapol as aNanoparticulate Stabilizer;” U.S. Pat. No. 5,447,710 for “Method forMaking Nanoparticulate X-Ray Blood Pool Contrast Agents Using HighMolecular Weight Non-ionic Surfactants;” U.S. Pat. No. 5,451,393 for“X-Ray Contrast Compositions Useful in Medical Imaging;” U.S. Pat. No.5,466,440 for “Formulations of Oral Gastrointestinal Diagnostic X-RayContrast Agents in Combination with Pharmaceutically Acceptable Clays;”U.S. Pat. No. 5,470,583 for “Method of Preparing NanoparticleCompositions Containing Charged Phospholipids to Reduce Aggregation;”U.S. Pat. No. 5,472,683 for “Nanoparticulate Diagnostic Mixed CarbamicAnhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic SystemImaging;” U.S. Pat. No. 5,500,204 for “Nanoparticulate Diagnostic Dimersas X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;”U.S. Pat. No. 5,518,738 for “Nanoparticulate NSAID Formulations;” U.S.Pat. No. 5,521,218 for “Nanoparticulate Iododipamide Derivatives for Useas X-Ray Contrast Agents;” U.S. Pat. No. 5,525,328 for “NanoparticulateDiagnostic Diatrizoxy Ester X-Ray Contrast Agents for Blood Pool andLymphatic System Imaging;” U.S. Pat. No. 5,543,133 for “Process ofPreparing X-Ray Contrast Compositions Containing Nanoparticles;” U.S.Pat. No. 5,552,160 for “Surface Modified NSAID Nanoparticles;” U.S. Pat.No. 5,560,931 for “Formulations of Compounds as NanoparticulateDispersions in Digestible Oils or Fatty Acids;” U.S. Pat. No. 5,565,188for “Polyalkylene Block Copolymers as Surface Modifiers forNanoparticles;” U.S. Pat. No. 5,569,448 for “Sulfated Non-ionic BlockCopolymer Surfactant as Stabilizer Coatings for NanoparticleCompositions;” U.S. Pat. No. 5,571,536 for “Formulations of Compounds asNanoparticulate Dispersions in Digestible Oils or Fatty Acids;” U.S.Pat. No. 5,573,749 for “Nanoparticulate Diagnostic Mixed CarboxylicAnydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic SystemImaging;” U.S. Pat. No. 5,573,750 for “Diagnostic Imaging X-Ray ContrastAgents;” U.S. Pat. No. 5,573,783 for “Redispersible Nanoparticulate FilmMatrices With Protective Overcoats;” U.S. Pat. No. 5,580,579 for“Site-specific Adhesion Within the GI Tract Using NanoparticlesStabilized by High Molecular Weight, Linear Poly(ethylene Oxide)Polymers;” U.S. Pat. No. 5,585,108 for “Formulations of OralGastrointestinal Therapeutic Agents in Combination with PharmaceuticallyAcceptable Clays;” U.S. Pat. No. 5,587,143 for “Butylene Oxide-EthyleneOxide Block Copolymers Surfactants as Stabilizer Coatings forNanoparticulate Compositions;” U.S. Pat. No. 5,591,456 for “MilledNaproxen with Hydroxypropyl Cellulose as Dispersion Stabilizer;” U.S.Pat. No. 5,593,657 for “Novel Barium Salt Formulations Stabilized byNon-ionic and Anionic Stabilizers;” U.S. Pat. No. 5,622,938 for “SugarBased Surfactant for Nanocrystals;” U.S. Pat. No. 5,628,981 for“Improved Formulations of Oral Gastrointestinal Diagnostic X-RayContrast Agents and Oral Gastrointestinal Therapeutic Agents;” U.S. Pat.No. 5,643,552 for “Nanoparticulate Diagnostic Mixed Carbonic Anhydridesas X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;”U.S. Pat. No. 5,718,388 for “Continuous Method of GrindingPharmaceutical Substances;” U.S. Pat. No. 5,718,919 for “NanoparticlesContaining the R(-)Enantiomer of Ibuprofen;” U.S. Pat. No. 5,747,001 for“Aerosols Containing Beclomethasone Nanoparticle Dispersions;” U.S. Pat.No. 5,834,025 for “Reduction of Intravenously AdministeredNanoparticulate Formulation Induced Adverse Physiological Reactions;”U.S. Pat. No. 6,045,829 “Nanocrystalline Formulations of HumanImmunodeficiency Virus (HIV) Protease Inhibitors Using CellulosicSurface Stabilizers;” U.S. Pat. No. 6,068,858 for “Methods of MakingNanocrystalline Formulations of Human Immunodeficiency Virus (HIV)Protease Inhibitors Using Cellulosic Surface Stabilizers;” U.S. Pat. No.6,153,225 for “Injectable Formulations of Nanoparticulate Naproxen;”U.S. Pat. No. 6,165,506 for “New Solid Dose Form of NanoparticulateNaproxen;” U.S. Pat. No. 6,221,400 for “Methods of Treating MammalsUsing Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV)Protease Inhibitors;” U.S. Pat. No. 6,264,922 for “Nebulized AerosolsContaining Nanoparticle Dispersions;” U.S. Pat. No. 6,267,989 for“Methods for Preventing Crystal Growth and Particle Aggregation inNanoparticle Compositions;” U.S. Pat. No. 6,270,806 for “Use ofPEG-Derivatized Lipids as Surface Stabilizers for NanoparticulateCompositions;” U.S. Pat. No. 6,316,029 for “Rapidly Disintegrating SolidOral Dosage Form,” U.S. Pat. No. 6,375,986 for “Solid DoseNanoparticulate Compositions Comprising a Synergistic Combination of aPolymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate;” U.S.Pat. No. 6,428,814 for “Bioadhesive Nanoparticulate Compositions HavingCationic Surface Stabilizers;” U.S. Pat. No. 6,431,478 for “Small ScaleMill;” and U.S. Pat. No. 6,432,381 for “Methods for Targeting DrugDelivery to the Upper and/or Lower Gastrointestinal Tract,” all of whichare specifically incorporated by reference. In addition, U.S. patentapplication No. 20020012675 A1, published on Jan. 31, 2002, for“Controlled Release Nanoparticulate Compositions,” describesnanoparticulate compositions, and is specifically incorporated byreference.

Amorphous small particle compositions are described, for example, inU.S. Pat. No. 4,783,484 for “Particulate Composition and Use Thereof asAntimicrobial Agent;” U.S. Pat. No. 4,826,689 for “Method for MakingUniformly Sized Particles from Water-Insoluble Organic Compounds;” U.S.Pat. No. 4,997,454 for “Method for Making Uniformly-Sized Particles FromInsoluble Compounds;” U.S. Pat. No. 5,741,522 for “Ultrasmall,Non-aggregated Porous Particles of Uniform Size for Entrapping GasBubbles Within and Methods;” and U.S. Pat. No. 5,776,496, for“Ultrasmall Porous Particles for Enhancing Ultrasound Back Scatter.”

B. Background Regarding Fenofibrate

The compositions of the invention comprise a fibrate, preferablyfenofibrate. Fenofibrate, also known as2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethylester, is a lipid regulating agent. The compound is insoluble in water.See The Physicians' Desk Reference, 56^(th) Ed., pp. 513-516 (2002).

Fenofibrate is described in, for example, U.S. Pat. No. 3,907,792 for“Phenoxy-Alkyl-Carboxylic Acid Derivatives and the Preparation Thereof;”U.S. Pat. No. 4,895,726 for “Novel Dosage Form of Fenofibrate;” U.S.Pat. Nos. 6,074,670 and 6,277,405, both for “Fenofibrate PharmaceuticalComposition Having High Bioavailability and Method for Preparing It.”U.S. Pat. No. 3,907,792 describes a class of phenoxy-alkyl carboxyliccompounds which encompasses fenofibrate. U.S. Pat. No. 4,895,726describes a gelatin capsule therapeutic composition, useful in the oraltreatment of hyerlipidemia and hypercholesterolemia, containingmicronized fenofibrate. U.S. Pat. No. 6,074,670 refers toimmediate-release fenofibrate compositions comprising micronizedfenofibrate and at least one inert hydrosoluble carrier. U.S. Pat. No.4,739,101 describes a process for making fenofibrate. U.S. Pat. No.6,277,405 is directed to micronized fenofibrate compositions having aspecified dissolution profile. In addition, International PublicationNo. WO 02/24193 for “Stabilised Fibrate Microparticles,” published onMar. 28, 2002, describes a microparticulate fenofibrate compositioncomprising a phospholipid. Finally, International Publication No. WO02/067901 for “Fibrate-Statin Combinations with Reduced Fed-FastedEffects,” published on Sep. 6, 2002, describes a microparticulatefenofibrate composition comprising a phospholipid and ahydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor orstatin.

WO 01/80828 for “Improved Water-Insoluble Drug Particle Process,” andInternational Publication No. WO 02/24193 for “Stabilised FibrateMicroparticles,” describe a process for making small particlecompositions of poorly water soluble drugs. The process requirespreparing an admixture of a drug and one or more surface active agents,followed by heating the drug admixture to at or above the melting pointof the poorly water soluble drug. The heated suspension is thenhomogenized. The use of such a heating process is undesirable, asheating a drug to its melting point destroys the crystalline structureof the drug. Upon cooling, a drug may be amorphous or recrystallize in adifferent isoform, thereby producing a composition which is physicallyand structurally different from that desired. Such a “different”composition may have different pharmacological properties. This issignificant as U.S. Food and Drug Administration (USFDA) approval of adrug substance requires that the drug substance be stable and producedin a repeatable process.

WO 03/013474 for “Nanoparticulate Formulations of Fenofibrate,”published on Feb. 20, 2003, describes fibrate compositions comprisingvitamin E TGPS (polyethylene glycol (PEG) derivatized vitamin E). Thefibrate compositions of this reference comprise particles of fibrate andvitamin E TPGS having a mean diameter from about 100 nm to about 900 nm(page 8, lines 12-15, of WO 03/013474), a D₅₀ of 350-750 nm, and a D₉₉of 500 to 900 nm (page 9, lines 11-13, of WO 03/013474) (50% of theparticles of a composition fall below a “D₅₀”, and 99% of the particlesof a composition fall below a D₉₉). The reference does not teach thatthe described compositions show minimal or no variability whenadministered in fed as compared to fasted conditions.

A variety of clinical studies have demonstrated that elevated levels oftotal cholesterol (total-C), low density lipoprotein cholesterol(LDL-C), and apolipoprotein B (apo B), an LDL membrane complex, areassociated with human atherosclerosis. Similarly, decreased levels ofhigh density lipoprotein cholesterol (HDL-C) and its transport complex,apolipoprotein A (apo A2 and apo AII), are associated with thedevelopment of atherosclerosis. Epidemiologic investigations haveestablished that cardiovascular morbidity and mortality vary directlywith the level of total-C, LDL-C, and triglycerides, and inversely withthe level of HDL-C.

Fenofibric acid, the active metabolite of fenofibrate, producesreductions in total cholesterol, LDL cholesterol, apo-lipoprotein B,total triglycerides, and triglyceride rich lipoprotein (VLDL) in treatedpatients. In addition, treatment with fenofibrate results in increasesin high density lipoprotein (HDL) and apolipoprotein apoAI and apoAII.See The Physicians' Desk Reference, 56^(th) Ed., pp. 513-516 (2002).

Because fibrates, including fenofibrate, are so insoluble in water,significant bioavailability can be problematic. In addition,conventional fibrate, including fenofibrate, formulations exhibitdramatically different effects depending upon the fed or fasted state ofthe patient. Finally, conventional fibrate, including fenofibrate,formulations require relatively large doses to achieve the desiredtherapeutic effects. There is a need in the art for nanoparticulatefibrate formulations which overcome these and other problems associatedwith prior conventional microcrystalline fibrate formulations. Thepresent invention satisfies these needs.

SUMMARY OF THE INVENTION

The present invention relates to nanoparticulate compositions comprisinga fibrate, preferably fenofibrate. The compositions comprise a fibrate,preferably fenofibrate, and at least one surface stabilizer adsorbed onthe surface of the fibrate particles. The nanoparticulate fibrate,preferably fenofibrate, particles have an effective average particlesize of less than about 2000 nm.

A preferred dosage form of the invention is a solid dosage form,although any pharmaceutically acceptable dosage form can be utilized.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a nanoparticulate fibrate, preferablyfenofibrate, composition of the invention. The pharmaceuticalcompositions comprise a fibrate, preferably fenofibrate, at least onesurface stabilizer, and a pharmaceutically acceptable carrier, as wellas any desired excipients.

One embodiment of the invention encompasses a fibrate, preferablyfenofibrate, composition, wherein the pharmacokinetic profile of thefibrate is not affected by the fed or fasted state of a subjectingesting the composition, in particular as defined by C_(max) and AUCguidelines given by the U.S. Food and Drug Administration and thecorresponding European regulatory agency (EMEA).

Another aspect of the invention is directed to a nanoparticulatefibrate, preferably fenofibrate, composition having improvedpharmacokinetic profiles as compared to conventional microcrystallinefibrate formulations, such as T_(max), C_(max), and AUC.

In yet another embodiment, the invention encompasses a fibrate,preferably fenofibrate, composition, wherein administration of thecomposition to a subject in a fasted state is bioequivalent toadministration of the composition to a subject in a fed state, inparticular as defined by C_(max) and AUC guidelines given by the U.S.Food and Drug Administration and the corresponding European regulatoryagency (EMEA).

Another embodiment of the invention is directed to nanoparticulatefibrate, preferably fenofibrate, compositions additionally comprisingone or more compounds useful in treating dyslipidemia, hyperlipidemia,hypercholesterolemia, cardiovascular disorders, or related conditions.

Other embodiments of the invention include, but are not limited to,nanoparticulate fibrate, preferably fenofibrate, formulations which, ascompared to conventional non-nanoparticulate formulations of a fibrate,particularly a fenofibrate such as TRICOR® (160 mg tablet or 200 mgcapsule microcrystalline fenofibrate formulations), have one or more ofthe following properties: (1) smaller tablet or other solid dosage formsize; (2) smaller doses of drug required to obtain the samepharmacological effect; (3) increased bioavailability; (4) substantiallysimilar pharmacokinetic profiles of the nanoparticulate fibrate,preferably fenofibrate, compositions when administered in the fed versusthe fasted state; (5) an increased rate of dissolution for thenanoparticulate fibrate, preferably fenofibrate, compositions; and (6)bioadhesive fibrate, preferably fenofibrate, compositions.

This invention further discloses a method of making a nanoparticulatefibrate, preferably fenofibrate, composition according to the invention.Such a method comprises contacting a fibrate, preferably fenofibrate,and at least one surface stabilizer for a time and under conditionssufficient to provide a nanoparticulate fibrate composition, andpreferably a fenofibrate composition. The one or more surfacestabilizers can be contacted with a fibrate, preferably fenofibrate,either before, during, or after size reduction of the fibrate.

The present invention is also directed to methods of treatment using thenanoparticulate fibrate, preferably fenofibrate, compositions of theinvention for conditions such as hypercholesterolemia,hypertriglyceridemia, coronary heart disease, and peripheral vasculardisease (including symptomatic carotid artery disease). The compositionsof the invention can be used as adjunctive therapy to diet for thereduction of LDL-C, total-C, triglycerides, and Apo B in adult patientswith primary hypercholesterolemia or mixed dyslipidemia (FredricksonTypes IIa and IIb). The compositions can also be used as adjunctivetherapy to diet for treatment of adult patients withhypertriglyceridemia (Fredrickson Types IV and V hyperlipidemia).Markedly elevated levels of serum tryglycerides (e.g., >2000 mg/dL) mayincrease the risk of developing pancreatitis. Such methods compriseadministering to a subject a therapeutically effective amount of ananoparticulate fibrate, preferably fenofibrate, composition accordingto the invention. Other methods of treatment using the nanoparticulatecompositions of the invention are know to those of skill in the art.

Both the foregoing general description and the following detaileddescription are exemplary and explanatory and are intended to providefurther explanation of the invention as claimed. Other objects,advantages, and novel features will be readily apparent to those skilledin the art from the following detailed description of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Shows the fenofibric acid concentration (μg/ml) over a period of120 minutes for a single dose of: (a) a 160 mg nanoparticulatefenofibrate tablet administered to a fasting subject; (b) a 160 mgnanoparticulate fenofibrate tablet administered to a high fat fedsubject; and (c) a 200 mg microcrystalline (TRICOR®; AbbottLaboratories, Abbott Park, Ill.) capsule administered to a low fat fedsubject; and

FIG. 2: Shows the fenofibric acid concentration (μg/ml) over a period of24 hours for a single dose of: (a) a 160 mg nanoparticulate fenofibratetablet administered to a fasting subject; (b) a 160 mg nanoparticulatefenofibrate tablet administered to a high fat fed subject; and (c) a 200mg microcrystalline (TRICOR®) capsule administered to a low fat fedsubject.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to nanoparticulate compositionscomprising a fibrate, preferably fenofibrate. The compositions comprisea fibrate, preferably fenofibrate, and preferably at least one surfacestabilizer adsorbed on the surface of the drug. The nanoparticulatefibrate, preferably fenofibrate, particles have an effective averageparticle size of less than about 2000 nm.

As taught in the '684 patent, and as exemplified in the examples below,not every combination of surface stabilizer and active agent will resultin a stable nanoparticulate composition. It was surprisingly discoveredthat stable, nanoparticulate fibrate, preferably fenofibrate,formulations can be made.

Advantages of the nanoparticulate fibrate, preferably fenofibrate,formulations of the invention as compared to conventionalnon-nanoparticulate formulations of a fibrate, particularly afenofibrate such as TRICOR® (tablet or capsule microcrystallinefenofibrate formulations), include, but are not limited to: (1) smallertablet or other solid dosage form size; (2) smaller doses of drugrequired to obtain the same pharmacological effect; (3) increasedbioavailability; (4) substantially similar pharmacokinetic profiles ofthe nanoparticulate fibrate, preferably fenofibrate, compositions whenadministered in the fed versus the fasted state; (5) improvedpharmacokinetic profiles; (6) bioequivalency of the nanoparticulatefibrate, preferably fenofibrate, compositions when administered in thefed versus the fasted state; (7) an increased rate of dissolution forthe nanoparticulate fibrate, preferably fenofibrate, compositions; (8)bioadhesive fibrate, preferably fenofibrate, compositions; and (9) thenanoparticulate fibrate, preferably fenofibrate, compositions can beused in conjunction with other active agents useful in treatingdyslipidemia, hyperlipidemia, hypercholesterolemia, cardiovasculardisorders, or related conditions.

The present invention also includes nanoparticulate fibrate, preferablyfenofibrate, compositions together with one or more non-toxicphysiologically acceptable carriers, adjuvants, or vehicles,collectively referred to as carriers. The compositions can be formulatedfor parenteral injection (e.g., intravenous, intramuscular, orsubcutaneous), oral administration in solid, liquid, or aerosol form,vaginal, nasal, rectal, ocular, local (powders, ointments or drops),buccal, intracisternal, intraperitoneal, or topical administration, andthe like.

A preferred dosage form of the invention is a solid dosage form,although any pharmaceutically acceptable dosage form can be utilized.Exemplary solid dosage forms include, but are not limited to, tablets,capsules, sachets, lozenges, powders, pills, or granules, and the soliddosage form can be, for example, a fast melt dosage form, controlledrelease dosage form, lyophilized dosage form, delayed release dosageform, extended release dosage form, pulsatile release dosage form, mixedimmediate release and controlled release dosage form, or a combinationthereof. A solid dose tablet formulation is preferred.

The present invention is described herein using several definitions, asset forth below and throughout the application.

As used herein, “about” will be understood by persons of ordinary skillin the art and will vary to some extent on the context in which it isused. If there are uses of the term which are not clear to persons ofordinary skill in the art given the context in which it is used, “about”will mean up to plus or minus 10% of the particular term.

As used herein with reference to stable fibrate, preferably fenofibrate,particles, “stable” includes, but is not limited to, one or more of thefollowing parameters: (1) that the fibrate particles do not appreciablyflocculate or agglomerate due to interparticle attractive forces, orotherwise significantly increase in particle size over time; (2) thatthe physical structure of the fibrate, preferably fenofibrate, particlesis not altered over time, such as by conversion from an amorphous phaseto crystalline phase; (3) that the fibrate, preferably fenofibrate,particles are chemically stable; and/or (4) where the fibrate has notbeen subject to a heating step at or above the melting point of thefibrate in the preparation of the nanoparticles of the invention.

A. Preferred Characteristics of the Fibrate Compositions of theInvention

1. Increased Bioavailability

The fibrate, preferably fenofibrate, formulations of the inventionexhibit increased bioavailability, at the same dose of the same fibrate,and require smaller doses as compared to prior conventional fibrate,preferably fenofibrate, formulations.

For example, as shown below in Example 6, administration of a 160 mgnanoparticulate fenofibrate tablet in a fasted state is notbioequivalent to administration of a 200 mg conventionalmicrocrystalline fenofibrate capsule (TRICOR®) in a fed state, pursuantto regulatory guidelines. Under U.S. FDA guidelines, two products ormethods are bioequivalent if the 90% Confidence Intervals (CI) for AUCand C_(max) are between 0.80 to 1.25 (T_(max) measurements are notrelevant to bioequivalence for regulatory purposes). To showbioequivalency between two compounds or administration conditionspursuant to Europe's EMEA guidelines, the 90% CI for AUC must be between0.80 to 1.25 and the 90% CI for C_(max) must between 0.70 to 1.43.

The non-bioequivalence is significant because it means that thenanoparticulate fenofibrate dosage form exhibits significantly greaterdrug absorption. For the nanoparticulate fenofibrate dosage form to bebioequivalent to the conventional microcrystalline fenofibrate dosageform (e.g., TRICOR®) the nanoparticulate fenofibrate dosage form wouldhave to contain significantly less drug. Thus, the nanoparticulatefenofibrate dosage form significantly increases the bioavailability ofthe drug.

Moreover, as shown below in Example 6, administration of a 160 mgnanoparticulate fenofibrate tablet in a fed state is bioequivalent toadministration of a 200 mg conventional microcrystalline fenofibratecapsule (TRICOR®) in a fed state. Thus, the nanoparticulate fenofibratedosage form requires less drug to obtain the same pharmacological effectobserved with the conventional microcrystalline fenofibrate dosage form(e.g., TRICOR®). Therefore, the nanoparticulate fenofibrate dosage formhas an increased bioavailability as compared to the conventionalmicrocrystalline fenofibrate dosage form (e.g., TRICOR®).

Greater bioavailability of the fibrate compositions of the invention canenable a smaller solid dosage size. This is particularly significant forpatient populations such as the elderly, juvenile, and infant. In oneembodiment of the invention, disclosed is a stable solid dosefenofibrate composition comprising: (a) a therapeutically effectivedosage of 145 mg of particles of fenofibrate or a salt thereof; and (b)associated with the surface thereof at least one surface stabilizer.Characteristics of the composition include: (i) the fenofibrateparticles have an effective average particle size of less than about2000 nm; (ii) the solid dose is bioequivalent to the TRICOR® 160 mgtablet, wherein bioequivalency is established by a 90% ConfidenceInterval of between 0.80 and 1.25 for both C_(max) and AUC or a 90%Confidence Interval of between 0.80 and 1.25 for AUC and a 90%Confidence Interval of between 0.70 to 1.43 for C_(max); and (iii) thesolid dose is about 10% smaller than the TRICOR® tablet. In anotherembodiment of the invention, disclosed is a stable solid dosefenofibrate composition comprising: (a) a therapeutically effectivedosage of 48 mg of particles of fenofibrate or a salt thereof; and (b)associated with the surface thereof at least one surface stabilizer.Characteristics of the composition include: (i) the fenofibrateparticles have an effective average particle size of less than about2000 nm; (ii) the solid dose is bioequivalent to the TRICOR® 54 mgtablet, wherein bioequivalency is established by a 90% ConfidenceInterval of between 0.80 and 1.25 for both C_(max) and AUC or a 90%Confidence Interval of between 0.80 and 1.25 for AUC and a 90%Confidence Interval of between 0.70 to 1.43 for C_(max); and (iii) thesolid dose is about 10% smaller than the TRICOR® tablet.

2. Improved Pharmacokinetic Profiles

The invention also provides fibrate, preferably fenofibrate,compositions having a desirable pharmacokinetic profile whenadministered to mammalian subjects. The desirable pharmacokineticprofile of the fibrate, preferably fenofibrate, compositions comprisethe parameters: (1) that the T_(max) of a fibrate, preferablyfenofibrate, when assayed in the plasma of the mammalian subject, isless than about 6 to about 8 hours. Preferably, the T_(max) parameter ofthe pharmacokinetic profile is less than about 6 hours, less than about5 hours, less than about 4 hours, less than about 3 hours, less thanabout 2 hours, less than about 1 hour, or less than about 30 minutesafter administration. The desirable pharmacokinetic profile, as usedherein, is the pharmacokinetic profile measured after the initial doseof a fibrate, preferably fenofibrate. The compositions can be formulatedin any way as described below and as known to those of skill in the art.

Current marketed formulations of fenofibrate include tablets, ice.,TRICOR® tablets marketed by Abbott Laboratories. According to thedescription of TRICOR®, the pharmacokinetic profile of the tabletscontain parameters such that the median T_(max) is 6-8 hours (PhysiciansDesk Reference, 56^(th) Ed., 2002). Because the compound is virtuallyinsoluble in water, the absolute bioavailability of TRICOR® cannot bedetermined (Physicians Desk Reference, 56^(th) Ed., 2002). Thecompositions of the invention improve upon at least the T_(max)parameter of the pharmacokinetic profile of a fibrate, preferablyfenofibrate.

A preferred fibrate formulation, preferably a fenofibrate formulation,of the invention exhibits in comparative pharmacokinetic testing with astandard commercial formulation of the same fibrate, e.g., TRICOR®tablets from Abbott Laboratories for fenofibrate, a T_(max) not greaterthan about 90%, not greater than about 80%, not greater than about 70%,not greater than about 60%, not greater than about 50%, not greater thanabout 30%, or not greater than about 25% of the T_(max) exhibited by astandard commercial fibrate formulation, e.g., TRICOR® tablets forfenofibrate.

Any formulation giving the desired pharnacokinetic profile is suitablefor administration according to the present methods. Exemplary types offormulations giving such profiles are liquid dispersions, gels,aerosols, ointments, creams, solid dose forms, etc. of a nanoparticulatefibrate, preferably nanoparticulate fenofibrate.

In a preferred embodiment of the invention, a fenofibrate composition ofthe invention comprises fenofibrate or a salt thereof, which whenadministered to a human as a dose of about 160 mg presents an AUC ofabout 139 μg/mL.h.

In yet another preferred embodiment of the invention, a fenofibratecomposition of the invention comprises fenofibrate and has a C_(max)under fasted conditions which is greater than the C_(max) under high fatfed (HFF) conditions, when administered to a human.

3. The Pharmacokinetic Profiles of the Fibrate Compositions of theInvention are not Affected by the Fed or Fasted State of the SubjectIngesting the Compositions

The invention encompasses a fibrate, preferably fenofibrate, compositionwherein the pharmacokinetic profile of the fibrate is not substantiallyaffected by the fed or fasted state of a subject ingesting thecomposition, when administered to a human. This means that there is nosubstantial difference in the quantity of drug absorbed or the rate ofdrug absorption when the nanoparticulate fibrate, preferablyfenofibrate, compositions are administered in the fed versus the fastedstate.

For conventional fenofibrate formulations, i.e., TRICOR®, the absorptionof fenofibrate is increased by approximately 35% when administered withfood. This significant difference in absorption observed withconventional fenofibrate formulations is undesirable. The fibrate,preferably fenofibrate, formulations of the invention overcome thisproblem, as the fibrate formulations reduce or preferably substantiallyeliminate significantly different absorption levels when administeredunder fed as compared to fasting conditions when administered to ahuman.

In a preferred embodiment of the invention, a fenofibrate composition ofthe invention comprises about 145 mg of fenofibrate and exhibits minimalor no food effect when administered to a human. In another preferredembodiment of the invention, a fenofibrate composition of the inventioncomprises about 48 mg of fenofibrate and exhibits minimal or no foodeffect when administered to a human.

As shown in Example 6, the pharmacokinetic parameters of the fenofibratecompositions of the invention are the same when the composition isadministered in the fed and fasted states when administered to a human.Specifically, there was no substantial difference in the rate orquantity of drug absorption when the fenofibrate composition wasadministered in the fed versus the fasted state. Thus, the fibratecompositions, and preferably fenofibrate compositions, of the inventionsubstantially eliminate the effect of food on the pharmacokinetics ofthe fibrate when administered to a human.

Benefits of a dosage form which substantially eliminates the effect offood include an increase in subject convenience, thereby increasingsubject compliance, as the subject does not need to ensure that they aretaking a dose either with or without food. This is significant, as withpoor subject compliance an increase in the medical condition for whichthe drug is being prescribed may be observed, i.e., cardiovascularproblems for poor subject compliance with a fibrate such as fenofibrate.

4. Bioequivalency of the Fibrate Compositions of the Invention WhenAdministered in the Fed Versus the Fasted State

The invention also encompasses a fibrate, preferably a fenofibrate,composition in which administration of the composition to a subject in afasted state is bioequivalent to administration of the composition to asubject in a fed state. “Bioequivalency” is established by a 90%Confidence Interval (CI) of between 0.80 and 1.25 for both C_(max) andAUC under USFDA regulatory guidelines, or a 90% CI for AUC of between0.80 to 1.25 and a 90% CI for C_(max) of between 0.70 to 1.43 under theEuropean EMEA regulatory guidelines.

The difference in absorption of the fibrate, preferably fenofibrate,compositions of the invention, when administered in the fed versus thefasted state, preferably is less than about 35%, less than about 30%,less than about 25%, less than about 20%, less than about 15%, less thanabout 10%, less than about 5%, or less than about 3%.

As shown in Example 6, administration of a fenofibrate compositionaccording to the invention in a fasted state was bioequivalent toadministration of a fenofibrate composition according to the inventionin a fed state, pursuant to regulatory guidelines. Under USFDAguidelines, two products or methods are bioequivalent if the 90%Confidence Intervals (CI) for C_(max) (peak concentration) and the AUC(area under the concentration/time curve) are between 0.80 to 1.25. ForEurope, the test for bioequivalency is if two products or methods have a90% CI for AUC of between 0.80 to 1.25 and a 90% CI for C_(max) ofbetween 0.70 to 1.43. The fibrate, preferably fenofibrate, compositionsof the invention meet both the U.S. and European guidelines forbioequivalency for administration in the fed versus the fasted state.

5. Dissolution Profiles of the Fibrate Compositions of the Invention

The fibrate, preferably fenofibrate, compositions of the invention have15 unexpectedly dramatic dissolution profiles. Rapid dissolution of anadministered active agent is preferable, as faster dissolution generallyleads to faster onset of action and greater bioavailability. To improvethe dissolution profile and bioavailability of fibrates, and inparticulate fenofibrate, it would be useful to increase the drug'sdissolution so that it could attain a level close to 100%.

The fibrate, preferably fenofibrate, compositions of the inventionpreferably have a dissolution profile in which within about 5 minutes atleast about 20% of the composition is dissolved. In other embodiments ofthe invention, at least about 30% or about 40% of the fibrate,preferably fenofibrate, composition is dissolved within about 5 minutes.In yet other embodiments of the invention, preferably at least about40%, about 50%, about 60%, about 70%, or about 80% of the fibrate,preferably fenofibrate, composition is dissolved within about 10minutes. Finally, in another embodiment of the invention, preferably atleast about 70%, about 80%, about 90%, or about 100% of the fibrate,preferably fenofibrate, composition is dissolved within about 20minutes.

Dissolution is preferably measured in a medium which is discriminating.Such a dissolution medium will produce two very different dissolutioncurves for two products having very different dissolution profiles ingastric juices; i.e., the dissolution medium is predictive of in vivodissolution of a composition. An exemplary dissolution medium is anaqueous medium containing the surfactant sodium lauryl sulfate at 0.025M. Determination of the amount dissolved can be carried out byspectrophotometry. The rotating blade method (European Pharmacopoeia)can be used to measure dissolution.

6. Redispersibility Profiles of the Fibrate Compositions of theInvention

An additional feature of the fibrate, preferably fenofibrate,compositions of the invention is that the compositions redisperse suchthat the effective average particle size of the redispersed fibrateparticles is less than about 2 microns. This is significant, as if uponadministration the nanoparticulate fibrate compositions of the inventiondid not redisperse to a substantially nanoparticulate particle size,then the dosage form may lose the benefits afforded by formulating thefibrate into a nanoparticulate particle size.

This is because nanoparticulate active agent compositions benefit fromthe small particle size of the active agent; if the active agent doesnot redisperse into the small particle sizes upon administration, then“clumps” or agglomerated active agent particles are formed, owing to theextremely high surface free energy of the nanoparticulate system and thethermodynamic driving force to achieve an overall reduction in freeenergy. With the formation of such agglomerated particles, thebioavailability of the dosage form may fall well below that observedwith the liquid dispersion form of the nanoparticulate active agent.

Moreover, the nanoparticulate fibrate, preferably fenofibrate,compositions of the invention exhibit dramatic redispersion of thenanoparticulate fibrate particles upon administration to a mammal, suchas a human or animal, as demonstrated by reconstitution/redispersion ina biorelevant aqueous media such that the effective average particlesize of the redispersed fibrate particles is less than about 2 microns.Such biorelevant aqueous media can be any aqueous media that exhibit thedesired ionic strength and pH, which form the basis for the biorelevanceof the media. The desired pH and ionic strength are those that arerepresentative of physiological conditions found in the human body. Suchbiorelevant aqueous media can be, for example, aqueous electrolytesolutions or aqueous solutions of any salt, acid, or base, or acombination thereof, which exhibit the desired pH and ionic strength.

Biorelevant pH is well known in the art. For example, in the stomach,the pH ranges from slightly less than 2 (but typically greater than 1)up to 4 or 5. In the small intestine the pH can range from 4 to 6, andin the colon it can range from 6 to 8. Biorelevant ionic strength isalso well known in the art. Fasted state gastric fluid has an ionicstrength of about 0.1M while fasted state intestinal fluid has an ionicstrength of about 0.14. See e.g., Lindahl et al., “Characterization ofFluids from the Stomach and Proximal Jejunum in Men and Women,” Pharm.Res., 14 (4): 497-502 (1997).

It is believed that the pH and ionic strength of the test solution ismore critical than the specific chemical content. Accordingly,appropriate pH and ionic strength values can be obtained throughnumerous combinations of strong acids, strong bases, salts, single ormultiple conjugate acid-base pairs (i.e., weak acids and correspondingsalts of that acid), monoprotic and polyprotic electrolytes, etc.

Representative electrolyte solutions can be, but are not limited to, HClsolutions, ranging in concentration from about 0.001 to about 0.1 M, andNaCl solutions, ranging in concentration from about 0.001 to about 0.1M, and mixtures thereof. For example, electrolyte solutions can be, butare not limited to, about 0.1 M HCl or less, about 0.01 M HCl or less,about 0.001 M HCl or less, about 0.1 M NaCl or less, about 0.01 M NaClor less, about 0.001 M NaCl or less, and mixtures thereof. Of theseelectrolyte solutions, 0.01 M HCl and/or 0.1 M NaCl, are mostrepresentative of fasted human physiological conditions, owing to the pHand ionic strength conditions of the proximal gastrointestinal tract.

Electrolyte concentrations of 0.001 M HCl, 0.01 M HCl, and 0.1 M HClcorrespond to pH 3, pH 2, and pH 1, respectively. Thus, a 0.01 M HClsolution simulates typical acidic conditions found in the stomach. Asolution of 0.1 M NaCl provides a reasonable approximation of the ionicstrength conditions found throughout the body, including thegastrointestinal fluids, although concentrations higher than 0.1 M maybe employed to simulate fed conditions within the human GI tract.

Exemplary solutions of salts, acids, bases or combinations thereof,which exhibit the desired pH and ionic strength, include but are notlimited to phosphoric acid/phosphate salts+sodium, potassium and calciumsalts of chloride, acetic acid/acetate salts+sodium, potassium andcalcium salts of chloride, carbonic acid/bicarbonate salts+sodium,potassium and calcium salts of chloride, and citric acid/citratesalts+sodium, potassium and calcium salts of chloride.

In other embodiments of the invention, the redispersed fibrate,preferably fenofibrate, particles of the invention (redispersed in anaqueous, biorelevant, or any other suitable media) have an effectiveaverage particle size of less than about 1900 nm, less than about 1800nm, less than about 1700 nm, less than about 1600 nm, less than about1500 nm, less than about 1400 nm, less than about 1300 nm, less thanabout 1200 nm, less than about 1100 nm, less than about 1000 nm, lessthan about 900 nm, less than about 800 nm, less than about 700 nm, lessthan about 600 nm, less than about 500 nm, less than about 400 nm, lessthan about 300 run, less than about 250 nm, less than about 200 nm, lessthan about 150 nm, less than about 100 nm, less than about 75 nm, orless than about 50 nm, as measured by light-scattering methods,microscopy, or other appropriate methods.

Redispersibility can be tested using any suitable means known in theart. See e.g., the example sections of U.S. Pat. No.6,375,986 for “SolidDose Nanoparticulate Compositions Comprising a Synergistic Combinationof a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate.”

7. Bioadhesive Fibrate Compositions

Bioadhesive fibrate, particularly fenofibrate, compositions of theinvention comprise at least one cationic surface stabilizer, which aredescribed in more detail below. Bioadhesive formulations of fibrate,particularly fenofibrate, exhibit exceptional bioadhesion to biologicalsurfaces, such as mucous. The term bioadhesion refers to any attractiveinteraction between two biological surfaces or between a biological anda synthetic surface. In the case of bioadhesive nanoparticulatecompositions, the term bioadhesion is used to describe the adhesionbetween the nanoparticulate fibrate, particularly fenofibrate,compositions and a biological substrate (i.e. gastrointestinal mucin,lung tissue, nasal mucosa, etc.). See e.g., U.S. Pat. No. 6,428,814 for“Bioadhesive Nanoparticulate Compositions Having Cationic SurfaceStabilizers,” which is specifically incorporated by reference.

There are basically two mechanisms which may be responsible for thisbioadhesion phenomena: mechanical or physical interactions and chemicalinteractions. The first of these, mechanical or physical mechanisms,involves the physical interlocking or interpenetration between abioadhesive entity and the receptor tissue, resulting from a goodwetting of the bioadhesive surface, swelling of the bioadhesive polymer,penetration of the bioadhesive entity into a crevice of the tissuesurface, or interpenetration of bioadhesive composition chains withthose of the mucous or other such related tissues. The second possiblemechanism of bioadhesion incorporates forces such as ionic attraction,dipolar forces, van der Waals interactions, and hydrogen bonds. It isthis form of bioadhesion which is primarily responsible for thebioadhesive properties of the nanoparticulate fibrate, preferablyfenofibrate, compositions of the invention. However, physical andmechanical interactions may also play a secondary role in thebioadhesion of such nanoparticulate compositions.

The bioadhesive fibrate, preferably fenofibrate, compositions of theinvention are useful in any situation in which it is desirable to applythe compositions to a biological surface. The bioadhesive fibrate,preferably fenofibrate, compositions coat the targeted surface in acontinuous and uniform film which is invisible to the naked human eye.

A bioadhesive fibrate, preferably fenofibrate, composition slows thetransit of the composition, and some fibrate particles would also mostlikely adhere to tissue other than the mucous cells and therefore give aprolonged exposure to the fibrate, thereby increasing absorption and thebioavailability of the administered dosage.

8. Fibrate Compositions Used in Conjunction with Other Active Agents

The fibrate, preferably fenofibrate, compositions of the invention canadditionally comprise one or more compounds useful in treatingdyslipidemia, hyperlipidemia, hypercholesterolemia, cardiovasculardisorders, or related conditions, or the fibrate, preferablyfenofibrate, compositions can be administered in conjunction with such acompound. Examples of such compounds include, but are not limited to,statins or HMG CoA reductase inhibitors and antihypertensives. Examplesof antihypertensives include, but are not limited to diuretics (“waterpills”), beta blockers, alpha blockers, alpha-beta blockers, sympatheticnerve inhibitors, angiotensin converting enzyme (ACE) inhibitors,calcium channel blockers, angiotensin receptor blockers (formal medicalname angiotensin-2-receptor antagonists, known as “sartans” for short).

Examples of statins or HMG CoA reductase inhibitors include, but are notlimited to, lovastatin; pravastatin; simavastatin; velostatin;atorvastatin (Lipitor®) and other6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones and derivatives, asdisclosed in U.S. Pat. No. 4,647,576); fluvastatin (Lescol®);fluindostatin (Sandoz XU-62-320); pyrazole analogs of mevalonolactonederivatives, as disclosed in PCT application WO 86/03488; rivastatin andother pyridyldihydroxyheptenoic acids, as disclosed in European Patent491226A; Searle's SC45355 (a 3-substituted pentanedioic acidderivative); dichloroacetate; imidazole analogs of mevalonolactone, asdisclosed in PCT application WO 86107054;3-carboxy-2-hydroxy-propane-phosphonic acid derivatives, as disclosed inFrench Patent No. 2,596,393; 2,3-di-substituted pyrrole, furan, andthiophene derivatives, as disclosed in European Patent Application No.0221025; naphthyl analogs of mevalonolactone, as disclosed in U.S. Pat.No. 4,686,237; octahydronaphthalenes, such as those disclosed in U.S.Pat. No. 4,499,289; keto analogs of mevinolin (lovastatin), as disclosedin European Patent Application No. 0,142,146 A2; phosphinic acidcompounds; as well as other HMG CoA reductase inhibitors.

B. Compositions

The invention provides compositions comprising fibrate, preferablyfenofibrate, particles and at least one surface stabilizer. The surfacestabilizers preferably are adsorbed on, or associated with, the surfaceof the fibrate, preferably fenofibrate, particles. Surface stabilizersespecially useful herein preferably physically adhere on, or associatewith, the surface of the nanoparticulate fibrate particles but do notchemically react with the fibrate particles or itself. Individuallyadsorbed molecules of the surface stabilizer are essentially free ofintermolecular cross-linkages.

The present invention also includes fibrate, preferably fenofibrate,compositions together with one or more non-toxic physiologicallyacceptable carriers, adjuvants, or vehicles, collectively referred to ascarriers. The compositions can be formulated for parenteral injection(e.g., intravenous, intramuscular, or subcutaneous), oral administrationin solid, liquid, or aerosol form, vaginal, nasal, rectal, ocular, local(powders, ointments or drops), buccal, intracisternal, intraperitoneal,or topical administration, and the like.

1. Fibrate Particles

As used herein the term “fibrate” means any of the fibric acidderivatives useful in the methods described herein, e.g., fenofibrate.Fenofibrate is a fibrate compound, other examples of which arebezafibrate, beclobrate, binifibrate, ciplofibrate, clinofibrate,clofibrate, clofibric acid, etofibrate, gemfibrozil, nicofibrate,pirifibrate, ronifibrate, simfibrate, theofibrate, etc. See U.S. Pat.No. 6,384,062.

Generally, fibrates are used for conditions such ashypercholesterolemia, mixed lipidemia, hypertriglyceridemia, coronaryheart disease, and peripheral vascular disease (including symptomaticcarotid artery disease), and prevention of pancreatitis. Fenofibrate mayalso help prevent the development of pancreatitis (inflammation of thepancreas) caused by high levels of triglycerides in the blood. Fibratesare known to be useful in treating renal failure (U.S. Pat. No.4,250,191). Fibrates may also be used for other indications where lipidregulating agents are typically used.

As used herein the term “fenofibrate” is used to mean fenofibrate(2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethylester) or a salt thereof.

Fenofibrate is well known in the art and is readily recognized by one ofordinary skill. It is used to lower triglyceride (fat-like substances)levels in the blood. Specifically, fenofibrate reduces elevated LDL-C,Total-C, triglycerides, and Apo-B and increases HDL-C. The drug has alsobeen approved as adjunctive therapy for the treatment ofhypertriglyceridemia, a disorder characterized by elevated levels ofvery low density lipoprotein (VLDL) in the plasma

The mechanism of action of fenofibrate has not been clearly establishedin man. Fenofibric acid, the active metabolite of fenofibrate, lowersplasma triglycerides apparently by inhibiting triglyceride synthesis,resulting in a reduction of VLDL released into the circulation, and alsoby stimulating the catabolism of triglyceride-rich lipoprotein (i.e.,VLDL). Fenofibrate also reduces serum uric acid levels in hyperuricemicand normal individuals by increasing the urinary excretion of uric acid.

The absolute bioavailability of conventional microcrystallinefenofibrate cannot be determined as the compound is virtually insolublein aqueous media suitable for injection. However, fenofibrate is wellabsorbed from the gastrointestinal tract. Following oral administrationin healthy volunteers, approximately 60% of a single dose ofconventional radiolabelled fenofibrate (i.e., TRICOR®) appeared inurine, primarily as fenofibric acid and its glucuronate conjugate, and25% was excreted in the feces. Seehttp://www.rxlist.com/cgi/generic3/fenofibrate_cp.htm

Following oral administration, fenofibrate is rapidly hydrolyzed byesterases to the active metabolite, fenofibric acid; no unchangedfenofibrate is detected in plasma. Fenofibric acid is primarilyconjugated with glucuronic acid and then excreted in urine. A smallamount of fenofibric acid is reduced at the carbonyl moiety to abenzhydrol metabolite which is, in turn, conjugated with glucuronic acidand excreted in urine. Id.

2. Surface Stabilizers

The choice of a surface stabilizer for a fibrate is non-trivial andrequired extensive experimentation to realize a desirable formulation.Accordingly, the present invention is directed to the surprisingdiscovery that nanoparticulate fibrate, preferably fenofibrate,compositions can be made.

Combinations of more than one surface stabilizer can be used in theinvention. Useful surface stabilizers which can be employed in theinvention include, but are not limited to, known organic and inorganicpharmaceutical excipients. Such excipients include various polymers, lowmolecular weight oligomers, natural products, and surfactants. Surfacestabilizers include nonionic, anionic, cationic, ionic, and zwitterionicsurfactants.

Representative examples of surface stabilizers useful in the inventioninclude, but are not limited to, hydroxypropyl methylcellulose (nowknown as hypromellose), hydroxypropylcellulose, polyvinylpyrrolidone,sodium lauryl sulfate, dioctylsulfosuccinate, gelatin, casein, lecithin(phosphatides), dextran, gum acacia, cholesterol, tragacanth, stearicacid, benzalkonium chloride, calcium stearate, glycerol monostearate,cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters,polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitanfatty acid esters (e.g., the commercially available Tweens® such ase.g., Tween 20® and Tween 80® (ICI Speciality Chemicals)); polyethyleneglycols (e.g., Carbowaxs 3550® and 934® (Union Carbide)),polyoxyethylene stearates, colloidal silicon dioxide, phosphates,carboxymethylcellulose calcium, carboxymethylcellulose sodium,methylcellulose, hydroxyethylcellulose, hypromellose phthalate,noncrystalline cellulose, magnesium aluminium silicate, triethanolamine,polyvinyl alcohol (PVA), 4-(1,1,3,3-tetramethylbutyl)-phenol polymerwith ethylene oxide and formaldehyde (also known as tyloxapol,superione, and triton), poloxamers (e.g., Pluronics F68® and F108®,which are block copolymers of ethylene oxide and propylene oxide);poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, whichis a tetrafunctional block copolymer derived from sequential addition ofpropylene oxide and ethylene oxide to ethylenediamine (BASF WyandotteCorporation, Parsippany, N.J.)); Tetronic 1508® (T-1508) (BASF WyandotteCorporation), Tritons X-200®, which is an alkyl aryl polyether sulfonate(Rohm and Haas); Crodestas F-110®, which is a mixture of sucrosestearate and sucrose distearate (Croda Inc.);p-isononylphenoxypoly-(glycidol), also known as Olin-1OG® or Surfactant10-G® (Olin Chemicals, Stamford, Conn.); Crodestas SL40® (Croda, Inc.);and SA9OHCO, which is C₁₈H₃₇CH₂(CON(CH₃)—CH₂(CHOH)₄(CH₂0H)₂ (EastmanKodak Co.); decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside;n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecylβ-D-maltoside; heptanoyl-N-methylglucamide;n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexylβ-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noylβ-D-glucopyranoside; octanoyl-N-methylglucamide;n-octyl-β-D-glucopyranoside; octyl β-D-thioglucopyranoside;PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative,PEG-vitamin A, PEG-vitamin E, lysozyme, random copolymers of vinylpyrrolidone and vinyl acetate, and the like.

If desirable, the nanoparticulate fibrate, preferable fenofibrate,compositions of the invention can be formulated to be phospholipid-free.

Examples of useful cationic surface stabilizers include, but are notlimited to, polymers, biopolymers, polysaccharides, cellulosics,alginates, phospholipids, and nonpolymeric compounds, such aszwitterionic stabilizers, poly-n-methylpyridinium, anthryul pyridiniumchloride, cationic phospholipids, chitosan, polylysine,polyvinylimidazole, polybrene, polymethylmethacrylatetrimethylammoniumbromide bromide (PMMTMABr), hexyldesyltrimethylammoniumbromide (HDMAB), and polyvinylpyrrolidone-2-dimethylaminoethylmethacrylate dimethyl sulfate.

Other useful cationic stabilizers include, but are not limited to,cationic lipids, sulfonium, phosphonium, and quaternary ammoniumcompounds, such as stearyltrimethylammonium chloride,benzyl-di(2-chloroethyl)etbylammonium bromide, coconut trimethylammonium chloride or bromide, coconut methyl dihydroxyethyl ammoniumchloride or bromide, decyl triethyl ammonium chloride, decyl dimethylhydroxyethyl ammonium chloride or bromide, C₁₂₋₁₅dimethyl hydroxyethylammonium chloride or bromide, coconut dimethyl hydroxyethyl ammoniumchloride or bromide, myristyl trimethyl ammonium methyl sulphate, lauryldimethyl benzyl ammonium chloride or bromide, lauryl dimethyl(ethenoxy)₄ammonium chloride or bromide, N-alkyl(C₁₂₋₁₈)dimethylbenzyl ammoniumchloride, N-alkyl(C₁₄₋₁₈)dimethyl-benzyl ammonium chloride,N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyldidecyl ammonium chloride, N-alkyl and (C₁₂₋₁₄) dimethyl 1-napthylmethylammonium chloride, trimethylammonium halide, alkyl-trimethylammoniumsalts and dialkyl-dimethylammonium salts, lauryl trimethyl ammoniumchloride, ethoxylated alkyamidoalkyldialkylammonium salt and/or anethoxylated trialkyl ammonium salt, dialkylbenzene dialkylammoniumchloride, N-didecyldimethyl ammonium chloride,N-tetradecyldimethylbenzyl ammonium, chloride monohydrate,N-alkyl(C₁₂₋₁₄) dimethyl 1-naphthylmethyl ammonium chloride anddodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammoniumchloride, lauryl trimethyl ammonium chloride, alkylbenzyl methylammonium chloride, alkyl benzyl dimethyl ammonium bromide, C₁₂, C₁₅, C₁₇trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride,poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammoniumchlorides, alkyldimethylammonium halogenides, tricetyl methyl ammoniumchloride, decyltrimethylammonium bromide, dodecyltriethylammoniumbromide, tetradecyltrimethylammonium bromide, methyl trioctylammoniumchloride (ALIQUAT 336™), POLYQUAT 10™, tetrabutylammonium bromide,benzyl trimethylammonium bromide, choline esters (such as choline estersof fatty acids), benzalkonium chloride, stearalkonium chloride compounds(such as stearyltrimonium chloride and Distearyldimonium chloride),cetyl pyridinium bromide or chloride, halide salts of quaternizedpolyoxyethylalkylamines, MIRAPOL™ and ALKAQUAT™ (Alkaril ChemicalCompany), alkyl pyridinium salts; amines, such as alkylamines,dialkylamines, alkanolamines, polyethylenepolyamines,N,N-dialkylaminoalkyl acrylates, and vinyl pyridine, amine salts, suchas lauryl amine acetate, stearyl amine acetate, alkylpyridinium salt,and alkylimidazolium salt, and amine oxides; imide azolinium salts;protonated quaternary acrylarnides; methylated quaternary polymers, suchas poly[diallyl dimethylammonium chloride] and poly-[N-methyl vinylpyridinium chloride]; and cationic guar.

Such exemplary cationic surface stabilizers and other useful cationicsurface stabilizers are described in J. Cross and E. Singer, CationicSurfactants: Analytical and Biological Evaluation (Marcel Dekker, 1994);P. and D. Rubingh (Editor), Cationic Surfactants: Physical Chemistry(Marcel Dekker, 1991); and J. Richmond, Cationic Surfactants: OrganicChemistry, (Marcel Dekker, 1990).

Nonpolymeric surface stabilizers are any nonpolymeric compound, suchbenzalkonium chloride, a carbonium compound, a phosphonium compound, anoxonium compound, a halonium compound, a cationic organometalliccompound, a quarternary phosphorous compound, a pyridinium compound, ananilinium compound, an ammonium compound, a hydroxylammonium compound, aprimary ammonium compound, a secondary ammonium compound, a tertiaryammonium compound, and quarternary ammonium compounds of the formulaNR₁R₂R₃R₄ ⁽⁺⁾. For compounds of the formula NR₁R₂R₃R₄ ^((+):)

-   -   (i) none of R₁—R₄ are CH₃;    -   (ii) one of R₁—R₄ is CH₃;    -   (iii) three of R₁—R₄ are CH₃;    -   (iv) all of R₁—R₄ are CH₃;    -   (v) two of R₁—R₄ are CH₃, one of R₁—R₄ is C₆H₅CH₂, and one of        R₁—R₄ is an alkyl chain of seven carbon atoms or less;    -   (vi) two of R₁—R₄ are CH₃, one of R₁—R₄ is C₆H₅CH₂, and one of        R₁—R₄ is an alkyl chain of nineteen carbon atoms or more;    -   (vii) two of R₁—R₄ are CH₃ and one of R₁—R₄ is the group        C₆H₅(CH₂)_(n), where n>1;    -   (viii) two of R₁—R₄ are CH₃, one of R₁—R₄ is C₆H₅CH₂, and one of        R₁—R₄ comprises at least one heteroatom;    -   (ix) two of R₁—R₄ are CH₃, one of R₁—R₄ is C₆H₅CH₂, and one of        R₁—R₄ comprises at least one halogen;    -   (x) two of R₁—R₄ are CH₃, one of R₁—R₄ is C₆H₅CH₂, and one of        R₁—R₄ comprises at least one cyclic fragment;    -   (xi) two of R₁—R₄ are CH₃ and one of R₁—R₄ is a phenyl ring; or    -   (xii) two of R₁—R₄ are CH₃ and two of R₁—R₄ are purely aliphatic        fragments.

Such compounds include, but are not limited to, behenalkonium chloride,benzethonium chloride, cetylpyridinium chloride, behentrimoniumchloride, lauralkonium chloride, cetalkonium chloride, cetrimoniumbromide, cetrimonium chloride, cethylamine hydrofluoride,chlorallylmethenamine chloride (Quatemium-15), distearyldimoniumchloride (Quatemium-5), dodecyl dimethyl ethylbenzyl ammoniumchloride(Quaternium-14), Quatemium-22, Quaternium-26, Quaternium-18hectorite, dimethylaminoethylchloride hydrochloride, cysteinehydrochloride, diethanolammonium POE (10) oletyl ether phosphate,diethanolammonium POE (3)oleyl ether phosphate, tallow alkoniumchloride, dimethyl dioctadecylammoniumbentonite, stearalkonium chloride,domiphen bromide, denatonium benzoate, myristalkonium chloride,laurtrimonium chloride, ethylenediamine dihydrochloride, guanidinehydrochloride, pyridoxine HCl, iofetamine hydrochloride, megluminehydrochloride, methylbenzethonium chloride, myrtrimonium bromide,oleyltrimonium chloride, polyquaternium-1, procainehydrochloride,cocobetaine, stearalkonium bentonite, stearalkoniumhectonite, stearyltrihydroxyethyl propylenediarnine dihydrofluoride, tallowtrimoniumchloride, and hexadecyltrimethyl ammonium bromide.

In one embodiment of the invention, the preferred one or more surfacestabilizers of the invention is any suitable surface stabilizer asdescribed below, with the exclusion of PEG-derivatized vitamin E, whichis a non-ionic compound. In another embodiment of the invention, thepreferred one or more surface stabilizers of the invention is anysuitable surface stabilizer as described below, with the exclusion ofphospholipids. Finally, in another embodiment of the invention, thepreferred one or more surface stabilizers of the invention is anysubstance which is categorized by the USFDA as GRAS (“GenerallyRecognized As Safe”).

Preferred surface stabilizers of the invention include, but are notlimited to, hypromellose, docusate sodium (DOSS), Plasdone® S630 (randomcopolymer of vinyl pyrrolidone and vinyl acetate in a 60:40 ratio),hydroxypropyl cellulose SL (HPC-SL), sodium lauryl sulfate (SLS), andcombinations thereof. Particularly preferred combinations of surfacestabilizers include, but are not limited to, hypromellose and DOSS;Plasdone® S630 and DOSS; HPC-SL and DOSS; and hypromellose, DOSS, andSLS.

The surface stabilizers are commercially available and/or can beprepared by techniques known in the art. Most of these surfacestabilizers are known pharmaceutical excipients and are described indetail in the Handbook of Pharmaceutical Excipients, published jointlyby the American Pharmaceutical Association and The PharmaceuticalSociety of Great Britain (The Pharmaceutical Press, 2000), specificallyincorporated by reference.

3. Other Pharmaceutical Excipients

Pharmaceutical compositions according to the invention may also compriseone or more binding agents, filling agents, lubricating agents,suspending agents, sweeteners, flavoring agents, preservatives, buffers,wetting agents, disintegrants, effervescent agents, and otherexcipients. Such excipients are known in the art.

Examples of filling agents are lactose monohydrate, lactose anhydrous,and various starches; examples of binding agents are various cellulosesand cross-linked polyvinylpyrrolidone, microcrystalline cellulose, suchas Avicel® PH101 and Avicel® PH102, microcrystalline cellulose, andsilicified microcrystalline cellulose (ProSolv SMCC™).

Suitable lubricants, including agents that act on the flowability of thepowder to be compressed, are colloidal silicon dioxide, such as Aerosil®200, talc, stearic acid, magnesium stearate, calcium stearate, andsilica gel.

Examples of sweeteners are any natural or artificial sweetener, such assucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame.Examples of flavoring agents are Magnasweet® (trademark of MAFCO),bubble gum flavor, and fruit flavors, and the like.

Examples of preservatives are potassium sorbate, methylparaben,propylparaben, benzoic acid and its salts, other esters ofparahydroxybenzoic acid such as butylparaben, alcohols such as ethyl orbenzyl alcohol, phenolic compounds such as phenol, or quarternarycompounds such as benzalkonium chloride.

Suitable diluents include pharmaceutically acceptable inert fillers,such as microcrystalline cellulose, lactose, dibasic calcium phosphate,saccharides, and/or mixtures of any of the foregoing. Examples ofdiluents include microcrystalline cellulose, such as Avicel® PH101 andAvicel® PH102; lactose such as lactose monohydrate, lactose anhydrous,and Pharmatose® DCL21; dibasic calcium phosphate such as Emcompress®;mannitol; starch; sorbitol; sucrose; and glucose.

Suitable disintegrants include lightly crosslinked polyvinylpyrrolidone, corn starch, potato starch, maize starch, and modifiedstarches, croscarnellose sodium, cross-povidone, sodium starchglycolate, and mixtures thereof.

Examples of effervescent agents are effervescent couples such as anorganic acid and a carbonate or bicarbonate. Suitable organic acidsinclude, for example, citric, tartaric, malic, fumaric, adipic,succinic, and alginic acids and anhydrides and acid salts. Suitablecarbonates and bicarbonates include, for example, sodium carbonate,sodium bicarbonate, potassium carbonate, potassium bicarbonate,magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, andarginine carbonate. Alternatively, only the sodium bicarbonate componentof the effervescent couple may be present.

4. Nanoparticulate Fibrate Particle Size

The compositions of the invention contain nanoparticulate fibrateparticles, preferably nanoparticulate fenofibrate particles, which havean effective average particle size of less than about 2000 nm (i.e., 2microns), less than about 1900 nm, less than about 1800 nm, less thanabout 1700 nm, less than about 1600 nm, less than about 1500 nm, lessthan about 1400 nm, less than about 1300 nm, less than about 1200 nm,less than about 1100 nm, less than about 1000 nm, less than about 900nm, less than about 800 nm, less than about 700 nm, less than about 600nm, less than about 500 nm, less than about 400 nm, less than about 300nm, less than about 250 nm, less than about 200 nm, less than about 150nm, less than about 100 nm, less than about 75 nm, or less than about 50nm, as measured by light-scattering methods, microscopy, or otherappropriate methods.

By “an effective average particle size of less than about 2000 nm” it ismeant that at least 50% of the fibrate, preferably fenofibrate,particles have a particle size of less than the effective average, byweight, i.e., less than about 2000 nm, 1900 nm, 1800 nm, etc., whenmeasured by the above-noted techniques. Preferably, at least about 70%,about 90%, or about 95% of the fibrate, preferably fenofibrate,particles have a particle size of less than the effective average, i.e.,less than about 2000 nm, 1900 nm, 1800 nm, 1700 nm, etc.

In one embodiment of the invention, at least 99% of the fibrateparticles (D₉₉”) have a particle size less than about 500 nm, less thanabout 450 nm, less than about 400 nm, less than about 350 nm, less thanabout 300 nm, less than about 250 nm, less than about 200 nm, less thanabout 150 nm, or less than about 100 nm. In another embodiment of theinvention, at least 50% of the fibrate particles (“D₅₀”) have a particlesize less than about 350 nm, less than about 300 nm, less than about 250nm, less than about 200 nm, less than about 150 nm, less than about 100nm, or less than about 75 nm. In yet another embodiment of theinvention, the mean particle size of the fibrate composition is lessthan about 100 nm, less than about 75 nm, or less than about 50 nm.

In the present invention, the value for D₅₀ of a nanoparticulatefibrate, preferably fenofibrate, composition is the particle size belowwhich 50% of the fibrate particles fall, by weight. Similarly, D90 isthe particle size below which 90% of the fibrate particles fall, byweight.

5. Concentration of the Fibrate and Surface Stabilizers

The relative amounts of a fibrate, preferably fenofibrate, and one ormore surface stabilizers can vary widely. The optimal amount of theindividual components can depend, for example, upon the particularfibrate selected, the hydrophilic lipophilic balance (HLB), meltingpoint, and the surface tension of water solutions of the stabilizer,etc.

The concentration of the fibrate, preferably fenofibrate, can vary fromabout 99.5% to about 0.001%, from about 95% to about 0.1%, or from about90% to about 0.5%, by weight, based on the total combined weight of thefibrate and at least one surface stabilizer, not including otherexcipients.

The concentration of the at least one surface stabilizer can vary fromabout 0.5% to about 99.999%, from about 5.0% to about 99.9%, or fromabout 10% to about 99.5%, by weight, based on the total combined dryweight of the fibrate and at least one surface stabilizer, not includingother excipients.

6. Exemplary Nanoparticulate Fenofibrate Tablet Formulations

Several exemplary fenofibrate tablet formulations of the invention aregiven below. These examples are not intended to limit the claims in anyrespect, but rather provide exemplary tablet formulations of fenofibrateof the invention which can be utilized in the methods of the invention.Such exemplary tablets can also comprise a coating agent. ExemplaryNanoparticulate Fenofibrate Tablet Formulation #1 Component g/KgFenofibrate about 50 to about 500 Hypromellose, USP about 10 to about 70Docusate Sodium, USP about 1 to about 10 Sucrose, NF about 100 to about500 Sodium Lauryl Sulfate, NF about 1 to about 40 Lactose Monohydrate,NF about 50 to about 400 Silicified Microcrystalline Cellulose about 50to about 300 Crospovidone, NF about 20 to about 300 Magnesium Stearate,NF about 0.5 to about 5

Exemplary Nanoparticulate Fenofibrate Tablet Formulation #2 Componentg/Kg Fenofibrate about 100 to about 300 Hypromellose, USP about 30 toabout 50 Docusate Sodium, USP about 0.5 to about 10 Sucrose, NF about100 to about 300 Sodium Lauryl Sulfate, NF about 1 to about 30 LactoseMonohydrate, NF about 100 to about 300 Silicified MicrocrystallineCellulose about 50 to about 200 Crospovidone, NF about 50 to about 200Magnesium Stearate, NF about 0.5 to about 5

Exemplary Nanoparticulate Fenofibrate Tablet Formulation #3 Componentg/Kg Fenofibrate about 200 to about 225 Hypromellose, USP about 42 toabout 46 Docusate Sodium, USP about 2 to about 6 Sucrose, NF about 200to about 225 Sodium Lauryl Sulfate, NF about 12 to about 18 LactoseMonohydrate, NF about 200 to about 205 Silicified MicrocrystallineCellulose about 130 to about 135 Crospovidone, NF about 112 to about 118Magnesium Stearate, NF about 0.5 to about 3

Exemplary Nanoparticulate Fenofibrate Tablet Formulation #4 Componentg/Kg Fenofibrate about 119 to about 224 Hypromellose, USP about 42 toabout 46 Docusate Sodium, USP about 2 to about 6 Sucrose, NF about 119to about 224 Sodium Lauryl Sulfate, NF about 12 to about 18 LactoseMonohydrate, NF about 119 to about 224 Silicified MicrocrystallineCellulose about 129 to about 134 Crospovidone, NF about 112 to about 118Magnesium Stearate, NF about 0.5 to about 3D. Methods of Making Nanoparticulate Fibrate Compositions

The nanoparticulate fibrate, preferably fenofibrate, compositions can bemade using, for example, milling, homogenization, or precipitationtechniques. Exemplary methods of making nanoparticulate compositions aredescribed in the '684 patent. Methods of making nanoparticulatecompositions are also described in U.S. Pat. No. 5,518,187 for “Methodof Grinding Pharmaceutical Substances;” U.S. Pat. No. 5,718,388 for“Continuous Method of Grinding Pharmaceutical Substances;” U.S. Pat. No.5,862,999 for “Method of Grinding Pharmaceutical Substances;” U.S. Pat.No. 5,665,331 for “Co-Microprecipitation of NanoparticulatePharmaceutical Agents with Crystal Growth Modifiers;” U.S. Pat. No.5,662,883 for “Co-Microprecipitation of Nanoparticulate PharmaceuticalAgents with Crystal Growth Modifiers;” U.S. Pat. No. 5,560,932 for“Microprecipitation of Nanoparticulate Pharmaceutical Agents;” U.S. Pat.No. 5,543,133 for “Process of Preparing X-Ray Contrast CompositionsContaining Nanoparticles;” U.S. Pat. No. 5,534,270 for “Method ofPreparing Stable Drug Nanoparticles;” U.S. Pat. No. 5,510,118 for“Process of Preparing Therapeutic Compositions ContainingNanoparticles;” and U.S. Pat. No. 5,470,583 for “Method of PreparingNanoparticle Compositions Containing Charged Phospholipids to ReduceAggregation,” all of which are specifically incorporated by reference.

The resultant nanoparticulate fibrate, preferably fenofibrate,compositions or dispersions can be utilized in solid or liquid dosageformulations, such as liquid dispersions, gels, aerosols, ointments,creams, controlled release formulations, fast melt formulations,lyophilized formulations, tablets, capsules, delayed releaseformulations, extended release formulations, pulsatile releaseformulations, mixed immediate release and controlled releaseformulations, etc.

In one embodiment of the invention, if heat is utilized during theprocess of making the nanoparticulate composition, the temperature iskept below the melting point of the fibrate, preferably fenofibrate.

1. Milling to Obtain Nanoparticulate Fibrate Dispersions

Milling a fibrate, preferably fenofibrate, to obtain a nanoparticulatedispersion comprises dispersing the fibrate particles in a liquiddispersion medium in which the fibrate is poorly soluble, followed byapplying mechanical means in the presence of grinding media to reducethe particle size of the fibrate to the desired effective averageparticle size. The dispersion medium can be, for example, water,safflower oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG),hexane, or glycol. A preferred dispersion medium is water.

The fibrate, preferably fenofibrate, particles can be reduced in size inthe presence of at least one surface stabilizer. Alternatively, thefibrate particles can be contacted with one or more surface stabilizersafter attrition. Other compounds, such as a diluent, can be added to thefibrate/surface stabilizer composition during the size reductionprocess. Dispersions can be manufactured continuously or in a batchmode.

In one embodiment of the invention, a mixture of a fibrate and one ormore surface stabilizers is heated during the milling process. If apolymeric surface stabilizer is utilized, the temperature is raised toabove the cloud point of the polymeric surface stabilizer but below theactual or depressed melting point of the fibrate. The utilization ofheat may be important for scale up of the milling process, as it can aidin the solubilization of the one or more active agents.

2. Precipitation to Obtain Nanoparticulate Fibrate Compositions

Another method of forming the desired nanoparticulate fibrate,preferably fenofibrate, composition is by microprecipitation. This is amethod of preparing stable dispersions of poorly soluble active agentsin the presence of one or more surface stabilizers and one or morecolloid stability enhancing surface active agents free of any tracetoxic solvents or solubilized heavy metal impurities. Such a methodcomprises, for example: (1) dissolving a fibrate in a suitable solvent;(2) adding the formulation from step (1) to a solution comprising atleast one surface stabilizer; and (3) precipitating the formulation fromstep (2) using an appropriate non-solvent. The method can be followed byremoval of any formed salt, if present, by dialysis or diafiltration andconcentration of the dispersion by conventional means.

3. Homogenization to Obtain Nanoparticulate Fibrate Compositions

Exemplary homogenization methods of preparing active agentnanoparticulate compositions are described in U.S. Pat. No. 5,510,118,for “Process of Preparing Therapeutic Compositions ContainingNanoparticles.” Such a method comprises dispersing particles of afibrate, preferably fenofibrate, in a liquid dispersion medium, followedby subjecting the dispersion to homogenization to reduce the particlesize of the fibrate to the desired effective average particle size. Thefibrate particles can be reduced in size in the presence of at least onesurface stabilizer. Alternatively, the fibrate particles can becontacted with one or more surface stabilizers either before or afterattrition. Other compounds, such as a diluent, can be added to thefenofibrate/surface stabilizer composition either before, during, orafter the size reduction process. Dispersions can be manufacturedcontinuously or in a batch mode.

D. Methods of Using the Fibrate Compositions of the Invention

The invention provides a method of rapidly increasing the plasma levelsof a fibrate, preferably fenofibrate, in a subject. Such a methodcomprises orally administering to a subject an effective amount of acomposition comprising a fibrate, preferably fenofibrate. The fibratecomposition, when tested in fasting subjects in accordance with standardpharmacokinetic practice, produces a maximum blood plasma concentrationprofile in less than about 6 hours, less than about 5 hours, less thanabout 4 hours, less than about 3 hours, less than about 2 hours, lessthan about 1 hour, or less than about 30 minutes after the initial doseof the composition.

The compositions of the invention are useful in treating conditions suchas hypercholesterolemia, hypertriglyceridemia, cardiovascular disorders,coronary heart disease, and peripheral vascular disease (includingsymptomatic carotid artery disease). The compositions of the inventioncan be used as adjunctive therapy to diet for the reduction of LDL-C,total-C, triglycerides, and Apo B in adult patients with primaryhypercholesterolemia or mixed dyslipidemia (Fredrickson Types IIa andIIb). The compositions can also be used as adjunctive therapy to dietfor treatment of adult patients with hypertriglyceridemia (FredricksonTypes IV and V hyperlipidemia). Markedly elevated levels of serumtryglycerides (e.g., >2000 mg/dL) may increase the risk of developingpancreatitis. The compositions of the invention can also be used forother indications where lipid regulating agents are typically used.

The fenofibrate compositions of the invention can be administered to asubject via any conventional means including, but not limited to,orally, rectally, ocularly, parenterally (e.g., intravenous,intramuscular, or subcutaneous), intracistemally, pulmonary,intravaginally, intraperitoneally, locally (e.g., powders, ointments ordrops), or as a buccal or nasal spray. As used herein, the term“subject” is used to mean an animal, preferably a mammal, including ahuman or non-human. The terms patient and subject may be usedinterchangeably.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents,solvents, or vehicles including water, ethanol, polyols(propyleneglycol, polyethylene-glycol, glycerol, and the like), suitablemixtures thereof, vegetable oils (such as olive oil) and injectableorganic esters such as ethyl oleate. Proper fluidity can be maintained,for example, by the use of a coating such as lecithin, by themaintenance of the required particle size in the case of dispersions,and by the use of surfactants.

The nanoparticulate fibrate, preferably fenofibrate, compositions mayalso contain adjuvants such as preserving, wetting, emulsifying, anddispensing agents. Prevention of the growth of microorganisms can beensured by various antibacterial and antifungal agents, such asparabens, chlorobutanol, phenol, sorbic acid, and the like. It may alsobe desirable to include isotonic agents, such as sugars, sodiumchloride, and the like. Prolonged absorption of the injectablepharmaceutical form can be brought about by the use of agents delayingabsorption, such as aluminum monostearate and gelatin.

Solid dosage forms for oral administration include, but are not limitedto, capsules, tablets, pills, powders, and granules. In such soliddosage forms, the active agent is admixed with at least one of thefollowing: (a) one or more inert excipients (or carriers), such assodium citrate or dicalcium phosphate; (b) fillers or extenders, such asstarches, lactose, sucrose, glucose, mannitol, and silicic acid; (c)binders, such as carboxymethylcellulose, alignates, gelatin,polyvinylpyrrolidone, sucrose, and acacia; (d) humectants, such asglycerol; (e) disintegrating agents, such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain complexsilicates, and sodium carbonate; (f) solution retarders, such asparaffin; (g) absorption accelerators, such as quaternary ammoniumcompounds; (h) wetting agents, such as cetyl alcohol and glycerolmonostearate; (i) adsorbents, such as kaolin and bentonite; and (j)lubricants, such as talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, or mixtures thereof Forcapsules, tablets, and pills, the dosage forms may also comprisebuffering agents.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the fibrate, the liquid dosage forms may comprise inertdiluents commonly used in the art, such as water or other solvents,solubilizing agents, and emulsifiers. Exemplary emulsifiers are ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide, oils, such as cottonseed oil, groundnut oil, corngerm oil, olive oil, castor oil, and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols, fatty acid esters ofsorbitan, or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants,such as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

“Therapeutically effective amount” as used herein with respect to afibrate, preferably a fenofibrate, dosage shall mean that dosage thatprovides the specific pharmacological response for which the fibrate isadministered in a significant number of subjects in need of suchtreatment. It is emphasized that “therapeutically effective amount,”administered to a particular subject in a particular instance may not beeffective for 100% of patients treated for a specific disease, and willnot always be effective in treating the diseases described herein, eventhough such dosage is deemed a “therapeutically effective amount” bythose skilled in the art. It is to be further understood that fibratedosages are, in particular instances, measured as oral dosages, or withreference to drug levels as measured in blood.

One of ordinary skill will appreciate that effective amounts of afibrate, such as fenofibrate, can be determined empirically and can beemployed in pure form or, where such forms exist, in pharmaceuticallyacceptable salt, ester, or prodrug form. Actual dosage levels of afibrate, such as fenofibrate, in the nanoparticulate compositions of theinvention may be varied to obtain an amount of the fibrate that iseffective to obtain a desired therapeutic response for a particularcomposition and method of administration. The selected dosage leveltherefore depends upon the desired therapeutic effect, the route ofadministration, the potency of the administered fibrate, the desiredduration of treatment, and other factors.

Dosage unit compositions may contain such amounts of such submultiplesthereof as may be used to make up the daily dose. It will be understood,however, that the specific dose level for any particular patient willdepend upon a variety of factors: the type and degree of the cellular orphysiological response to be achieved; activity of the specific agent orcomposition employed; the specific agents or composition employed; theage, body weight, general health, sex, and diet of the patient; the timeof administration, route of administration, and rate of excretion of theagent; the duration of the treatment; drugs used in combination orcoincidental with the specific agent; and like factors well known in themedical arts.

The following examples are given to illustrate the present invention. Itshould be understood, however, that the invention is not to be limitedto the specific conditions or details described in these examples.Throughout the specification, any and all references to a publiclyavailable document, including a U.S. patent, are specificallyincorporated by reference.

Several of the formulations in the examples that follow wereinvestigated using a light microscope. Here, “stable” nanoparticulatedispersions (uniform Brownian motion) were readily distinguishable from“aggregated” dispersions (relatively large, nonuniform particles withoutmotion).

EXAMPLE 1

The purpose of this example was to prepare nanoparticulate dispersionsof fenofibrate, and to test the prepared compositions for stability inwater and in various simulated biological fluids.

Two formulations of fenofibrate were milled, as described in Table 1, bymilling the components of the compositions under high energy millingconditions in a DYNO®-Mill KDL (Willy A. Bachofen A G, Maschinenfabrik,Basle, Switzerland) for ninety minutes.

Formulation 1 comprised 5% (w/w) fenofibrate, 1% (w/w) hypromellose, and0.05% (w/w) dioctyl sodium sulfosuccinate (DOSS), and Formulation 2comprised 5% (w/w) fenofibrate, 1% (w/w) Pluronic® S-630 (a randomcopolymer of vinyl acetate and vinyl pyrrotidone), and 0.05% (w/w) DOSS.The particle size of the resultant compositions was measured using aHoriba LA-910 Laser Scattering Particle Size Distribution Analyzer((Horiba Instrumnents, Irvine, Calif.). TABLE 1 NanoparticulateFenofibrate Formulations Milled Under High Energy Conditions FormulationDrug Surface Stabilizer Particle Size 1 5% (w/w) 1% hypromellose Mean:139 nm and 0.05% DOSS 90% < 266 nm 2 5% (w/w) 1% S630 and Mean: 233 nm0.05% DOSS 90% < 355 nm

Next, the stability of the two formulations was tested in varioussimulated biological fluids (Table 2) and in water (Table 3) over anextended period of time. For tests in various simulated biologicalfluids, the composition was deemed stable if the particles remained in adispersion format with no visible size increase or agglomeration after30 min. incubation at 40° C. Testing in fluids representing electrolytefluids is useful as such fluids are representative of physiologicalconditions found in the human body. TABLE 2 Stability Testing ofNanoparticulate Fenofibrate Formulations 1 and 2 in Simulated BiologicalFluids Electrolyte Test Electrolyte Test Electrolyte Test FormulationMedia #1 Media #2 Media #3 1 Slight Agglomeration Acceptable Acceptable2 Heavy Agglomeration Acceptable Slight Agglomeration

TABLE 3 Stability Testing of Nanoparticulate Fenofibrate Formulations 1and 2 in Water at 2-8° C. Formulation 3 Days 1 Week 2 Weeks 7 Months 1Mean: 149 nm Mean: 146 nm Mean: 295 nm Mean: 1179 nm 90% < 289 nm 90% <280 nm 90% < 386 nm 90% < 2744 nm 2 Mean: 824 nm Mean: 927 nm Mean: 973nm Mean: 1099 nm 90% < 1357 nm 90% < 1476 nm 90% < 1526 nm 90% < 1681 nm

Stability results indicate that Formulation 1 is preferred overFormulation 2, as Formulation 2 exhibited slight agglomeration insimulated intestinal fluid and unacceptable particle size growth overtime.

EXAMPLE 2

The purpose of this example was to prepare nanoparticulate dispersionsof fenofibrate, followed by testing the stability of the compositions invarious simulated biological fluids.

Four formulations of fenofibrate were prepared, as described in Table 4,by milling the components of the compositions in a DYNO®-Mill KDL (WillyA. Bachofen A G, Maschinenfabrik, Basle, Switzerland) for ninetyminutes.

Formulation 3 comprised 5% (w/w) fenofibrate, 1% (w/w)hydroxypropylcellulose SL (HPC-SL), and 0.01% (w/w) DOSS; Formulation 4comprised 5% (w/w) fenofibrate, 1% (w/w) hypromellose, and 0.01% (w/w)DOSS; Formulation 5 comprised 5% (w/w) fenofibrate, 1% (w/w)polyvinylpyrrolidone (PVP K29/32), and 0.01% (w/w) DOSS; and Formulation6 comprised 5% (w/w) fenofibrate, 1% (w/w) Pluronic® S-630, and 0.01%(w/w) DOSS.

The particle size of the resultant compositions was measured using aHoriba LA-910 Laser Scattering Particle Size Distribution Analyzer((Horiba Instruments, Irvine, Calif.). TABLE 4 Particle Size ofNanoparticulate Fenofibrate Formulations Formulation Drug SurfaceStabilizer Particle Size 3 5% (w/w) 1% HPC-SL and Mean: 696 nm 0.01%DOSS 90% < 2086 nm 4 5% (w/w) 1% hypromellose Mean: 412 nm and 0.01%DOSS 90% < 502 nm 5 5% (w/w) 1% PVP and Mean: 4120 nm 0.01% DOSS 90% <9162 nm 6 5% (w/w) 1% S630 and Mean: 750 nm 0.01% DOSS 90% < 2184 nm

The results indicate that PVP is not a satisfactory surface stabilizerfor fenofibrate, at the particular concentrations of fenofibrate and PVPdisclosed, in combination with DOSS, as the mean particle size ofFormulation 5 was over two microns. However, PVP may be useful as asurface stabilizer for fenofibrate when it is used alone, in combinationwith another surface stabilizer, or when different concentrations of PVPand/or fenofibrate are utilized.

Next, the stability of Formulations 4 and 6 was tested in varioussimulated biological fluids (Table 5). TABLE 5 Stability Testing ofNanoparticulate Fenofibrate Formulations 3-6 in Simulated BiologicalFluids Electrolyte Test Electrolyte Test Electrolyte Test FormulationMedia #1 Media #2 Media #3 3 N/A N/A N/A 4 Acceptable AcceptableAcceptable 5 N/A N/A N/A 6 Agglomeration Very slight Slightagglomeration agglomeration

The results indicate that Formulation 4, comprising hypromellose andDOSS as surface stabilizers, is preferred as the initial particle sizeis within the useable range (i.e., 90%<512 nm) and the composition showsno aggregation in various simulated biological fluids.

The next set of examples relate to the redispersibility of the spraygranulated powders of the nanoparticulate fenofibrate compositions. Thepurpose for establishing redispersibility of the spray granulated powderis to determine whether the solid nanoparticulate fenofibratecomposition of the invention will redisperse when introduced into invitro or in vivo biologically relevant media.

EXAMPLE 3

The purpose of this example was to evaluate the redispersibility ofspray granulated powders of preferred nanoparticulate fenofibratecompositions comprising hypromellose and DOSS with or without SLS, apreferred small anionic surfactant.

The redispersibility of two powder forms of a spray granulated powder ofnanoparticulate fenofibrate was determined, the results of which areshown in Table 6. TABLE 6 Physical form Powder Powder Drug:Sucrose 1:0.61:1   Hypromellose:DOSS 1:0.2 — Hypromellose:DOSS + SLS — 1:0.3Redispersibility DI water Mean (nm) 390 182 D90 (nm) 418 260 % < 1000 nm95.9 100.0 Electrolyte Test Media #2 Mean (nm) 258 193 D90 (nm) 374 276% < 1000 nm 99.7 100.0 Electrolyte Test Media #3 Mean (nm) 287 225 D90(nm) 430 315 % < 1000 nm 99.6 100.0

The results show that powders prepared from a granulation feeddispersion having hypromellose, DOSS and SLS exhibit excellentredispersiblity.

EXAMPLE 4

The purpose of this example was to test the redispersibility of a spraygranulated powder of nanoparticulate fenofibrate comprising higherlevels of DOSS and SLS, as compared to Example 3. The results are shownin Table 7. TABLE 7 Physical form Powder Drug:Sucrose 1:1Hypromellose:SLS + DOSS 1:0.45 Redispersibility DI water Mean (nm) 196D90 (nm) 280 % <1000 nm 100 Electrolyte Test Media #2 Mean (nm) 222 D90(nm) 306 % <1000 nm 100 Electrolyte Test Media #3 Mean (nm) 258 D90 (nm)362 % <1000 nm 100

Excellent redispersibility was observed for all of the testedcompositions in simulated biological fluids.

EXAMPLE 5

The purpose of this example was to prepare a nanoparticulate fenofibratetablet formulation.

A fenofibrate nanoparticulate dispersion was prepared by combining thematerials listed in Table 8, followed by milling the mixture in aNetzsch LMZ2 Media Mill with Grinding Chamber with a flow rate of1.0±0.2 LPM and an agitator speed of 3000±100 RPM, utilizing DowPolyMill™ 500 micron milling media. The resultant mean particle size ofthe nanoparticulate fenofibrate dispersion (NCD), as measured by aHoriba LA-910 Laser Scattering Particle Size Distribution Analyzer((Horiba Instruments, Irvine, Calif.) was 169 nm. TABLE 8Nanoparticulate Fenofibrate Dispersion Fenofibrate 300 g/KgHypromellose, USP (Pharmacoat ® 603) 60 g/Kg Docusate Sodium, USP 0.75g/Kg Purified Water 639.25 g/Kg

Next, a granulated feed dispersion (GFD) was prepared by combining thenanoparticulate fenofibrate dispersion with the additional componentsspecified in Table 9. TABLE 9 Nanoparticulate Fenofibrate Granular FeedDispersion Nanoparticulate Fenofibrate Dispersion 1833.2 g Sucrose, NF550.0 g Sodium Lauryl Sulfate, NF 38.5 g Docusate Sodium, USP/EP 9.6 gPurified Water 723.2 g

The fenofibrate GFD was sprayed onto lactose monohydrate (500 g) to forma spray granulated intermediate (SGI) using a Vector Multi-1 Fluid BedSystem set to run at the parameters specified in Table 10, below. TABLE10 Fluid Bed System Parameters Inlet Air Temperature 70 ± 10° C.Exhaust/Product Air Temperature 37 ± 5° C. Air Volume 30 ± 20 CFM SprayRate 15 ± 10 g/min

The resultant spray granulated intermediate (SGI) of the nanoparticulatefenofibrate is detailed in Table 11, below. TABLE 11 Spray GranulatedIntermediate of the Nanoparticulate Fenofibrate Fenofibrate NCD 1833.2 gSucrose, NF 550.0 g Sodium Lauryl Sulfate, NF 38.5 g Docusate Sodium,USP/EP 9.6 g Lactose Monohydrate, NF 500 g

The nanoparticulate fenofibrate SGI was then tableted using a Kiliantablet press with a 0.700×0.300″ plain upper and lower caplet shapepunches. Each tablet has 160 mg of fenofibrate. The resulting tabletformulation is shown below in Table 12. TABLE 12 NanoparticulateFenofibrate Tablet Formulation Nanoparticulate Fenofibrate Spray 511.0mg Granulated Intermediate Silicified Microcrystalline Cellulose 95.0 mgCrospovidone, NF 83.0 mg Magnesium Stearate, NF 1.0 mg

EXAMPLE 6

The purpose of this example was to assess the effect of food on thebioavailability of a nanoparticulate fenofibrate tablet formulation, asprepared in Example 5.

Study Design

-   -   A single dose, three way cross-over design study, with eighteen        subjects, was conducted. The three treatments consisted of:    -   Treatment A: 160 mg nanoparticulate fenofibrate tablet        administered under fasted conditions;    -   Treatment B: 160 mg nanoparticulate fenofibrate tablet        administered under high fat fed conditions; and    -   Treatment C: 200 mg micronized fenofibrate capsule (TRICOR®)        administered under low fat fed conditions. “Low fat fed”        conditions are defined as 30% fat—400 Kcal, and “high fat fed”        conditions are defined as 50% fat—1000 Kcal. The length of time        between doses in the study was 10 days.

Results

FIG. 1 shows the plasma fenofibric acid profiles (i.e., the fenofibricacid concentration (μg/ml)) over a period of 120 hours for Treatment A,Treatment B, and Treatment C. FIG. 2 shows the same fenofibric acidprofiles, but over a 24 hour period rather than a 120 hour period.

Surprisingly, all three Treatments produce approximately the sameprofile, although the nanoparticulate fenofibrate tablet administeredunder fasting conditions exhibited a marginally higher maximumfenofibrate concentration. These results are significant for severalreasons. First, the nanoparticulate fenofibrate tablet is effective at alower dosage than that of the conventional microcrystalline fenofibratecapsule: 160 mg vs. 200 mg. A lower dosage is always seen as beneficialfor the patient, as less active agent is administered to the patient.

Second, the results show that the nanoparticulate fenofibrate tabletformulation does not exhibit significant differences in absorption whenadministered in the fed versus the fasted state. This is significant asit eliminates the need for a patient to ensure that they are taking adose with or without food. Therefore, the nanoparticulate fenofibratedosage form will result in increased patient compliance. With poorpatient compliance an increase in cardiovascular problems or otherconditions for which the fenofibrate is being prescribed can result.

The pharmacokinetic parameters of the three tests are shown below inTable 13. TABLE 13 Pharmacokinetic Parameters (Mean, Standard Deviation,CV %) Treatment A Treatment B Treatment C AUC (μg/mL · h) mean = 139.41mean = 138.55 mean = 142.96 SD = 45.04 SD = 41.53 SD = 51.28 CV % = 32%CV % = 30% CV % = 36% C_(max) (μg/mL) mean = 8.30 mean = 7.88 mean =7.08 SD = 1.37 SD = 1.74 SD = 1.72 CV % = 17% CV % = 22% CV % = 24%

The pharmacokinetic parameters first demonstrate that there is nodifference in the amount of drug absorbed when the nanoparticulatefenofibrate tablet is administered in the fed versus the fastedcondition (see the AUC results; 139.41 μg/mL.h for the dosage formadministered under fasted conditions and 138.55 μg/mL.h for the dosageform administered under fed conditions). Second, the data show thatthere was no difference in the rate of drug absorption when thenanoparticulate fenofibrate tablet is administered in the fed versus thefasted condition (see the C_(max) results; 8.30 μg/mL for the dosageform administered under fasted conditions and 7.88 μg/mL for the dosageform administered under fed conditions). Thus, the nanoparticulatefenofibrate dosage form eliminates the effect of food on thepharmacokinetics of fenofibrate. Accordingly, the invention encompassesa fibrate composition wherein the pharmacokinetic profile of the fibrateis not affected by the fed or fasted state of a subject ingesting thecomposition.

Bioequivalence of the Nanoparticulate Fenofibrate Dosage Form WhenAdministered in the Fed vs Fasted State

Using the data from Table 13, it was determined whether administrationof a nanoparticulate fenofibrate tablet in a fasted state wasbioequivalent to administration of a nanoparticulate fenofibrate tabletin a fed state, pursuant to regulatory guidelines. The relevant datefrom Table 13 is shown below in Table 14, along with the 90% ConfidenceIntervals (CI). Under U.S. FDA guidelines, two products or methods arebioequivalent if the 90% CI for AUC and C_(max) are between 0.80 to1.25. As shown below in Table 14, the 90% CI ratio for thenanoparticulate fenofibrate fed/fasted methods is 0.952:1.043 for AUCand 0.858:1.031 for C_(max). TABLE 14 Bioequivalence of NanoparticulateFenofibrate Tablet HFF vs. Nanoparticulate Fenofibrate Tablet Fasted CI90% on log- transformed data AUC (μg/mL · h) Nanoparticulate Fenofibrate139 0.952:1.043 Tablet 160 mg HFF Nanoparticulate Fenofibrate 139 Tablet160 mg Fasted Cmax (μg/mL) Nanoparticulate Fenofibrate 7.88 0.858:1.031Tablet 160 mg HFF Nanoparticulate Fenofibrate 8.30 Tablet 160 mg FastedAccordingly, pursuant to regulatory guidelines, administration of ananoparticulate fenofibrate tablet in a fasted state is bioequivalent toadministration of a nanoparticulate fenofibrate tablet in a fed state.Thus, the invention encompasses a fibrate composition whereinadministration of the composition to a subject in a fasted state isbioequivalent to administration of the composition to a subject in a fedstate.

Moreover, as shown by the data in Table 15 below, administration of a160 mg nanoparticulate fenofibrate tablet in a fed state isbioequivalent to administration of a 200 mg conventionalmicrocrystalline fenofibrate capsule (TRICOR®) in a fed state. This isbecause CI 90% for the two treatments is within 0.80 to 1.25 for AUC andC_(max). TABLE 15 Bioequivalence of Nanoparticulate 160 mg FenofibrateTablet HFF vs. a Microcrystalline 200 mg Fenofibrate Capsule (TRICOR ®)HFF CI 90% on log-transformed data AUC (μg/mL · h) Nanoparticulate 160mg 139 0.936:1.026 Fenofibrate Tablet HFF Microcrystalline 200 mg 143Fenofibrate Capsule (TRICOR ®) HFF Cmax (μg/mL) Nanoparticulate 160 mg7.88 1.020:1.226 Fenofibrate Tablet HFF Microcrystalline 200 mg 7.08Fenofibrate Capsule (TRICOR ®) HFF

Finally, as shown by the data in Table 16, below, administration of a160 mg nanoparticulate fenofibrate tablet in a fasted state is notbioequivalent to administration of a 200 mg conventionalmicrocrystalline fenofibrate capsule (TRICOR®) in a fed state. This isbecause CI 90% for the two treatments is outside 0.80 to 1.25 for AUCand C_(max). TABLE 16 Non-Bioequivalence of Nanoparticulate 160 mgFenofibrate Tablet Fasted vs. a Microcrystalline 200 mg FenofibrateCapsule (TRICOR ®) HFF CI 90% on log-transformed data AUC (μg/mL · h)Nanoparticulate 160 mg 139 0.939:1.030 Fenofibrate Tablet FastedMicrocrystalline 200 mg 143 Fenofibrate Capsule (TRICOR ®) HFF Cmax(μg/mL) Nanoparticulate 160 mg 8.30 1.084:1.304 Fenofibrate TabletFasted Microcrystalline 200 mg 7.08 Fenofibrate Capsule (TRICOR ®) HFF

The non-bioequivalence is significant, because it means that thenanoparticulate fenofibrate dosage form exhibits significantly greaterdrug absorption. For the nanoparticulate fenofibrate dosage form to bebioequivalent to the conventional microcrystalline fenofibrate dosageform (e.g., TRICOR®), the dosage form would have to containsignificantly less drug. Thus, the nanoparticulate fenofibrate dosageform significantly increases the bioavailability of the drug.

EXAMPLE 7

The purpose of this example was to provide nanoparticulate fenofibratetablet formulations prepared as described in Example 5, above.

Shown below in Table 17 is the nanoparticulate fenofibrate dispersionused for making the nanoparticulate fenofibrate tablet formulations.TABLE 17 Nanoparticulate Fenofibrate Dispersion Fenofibrate 194.0 g/KgHypromellose, USP (Pharmacoat ® 603) 38.81 g/Kg Docusate Sodium, USP0.485 g/Kg Water for injection, USP, EP 572.7 g/Kg Sucrose, NF 194.0g/Kg Actual Total 1000.0

Two different tablets were made using the dispersion: a 145 mgnanoparticulate fenofibrate tablet and a 48 mg nanoparticulatefenofibrate table.

A granulated feed dispersion (GFD) was prepared by combining thenanoparticulate fenofibrate dispersion with sucrose, docusate sodium,and sodium lauryl sulfate.

The fenofibrate GFD was processed and dried in a fluid-bed column(Vector Multi-1 Fluid Bed System), along with lactose monohydrate. Theresultant spray granulated intermediate (SGI) was processed through acone mill, followed by (1) processing in a bin blender with silicifiedmicrocrystalline cellulose and crospovidone, and (2) processing in a binblender with magnesium stearate. The resultant powder was tableted in arotary tablet press, followed by coating with Opadry® AMB using a pancoater.

Table 18 provides the composition of the 145 mg fenofibrate tablet, andTable 19 provides the composition of the 48 mg fenofibrate tablet. TABLE18 145 mg Nanoparticulate Fenofibrate Tablet Formulation Component g/KgFenofibrate 222.54 Hypromellose, USP 44.506 Docusate Sodium, USP 4.4378Sucrose, NF 222.54 Sodium Lauryl Sulfate, NF 15.585 Lactose Monohydrate,NF 202.62 Silicified Microcrystalline Cellulose 132.03 Crospovidone, NF115.89 Magnesium Stearate, NF 1.3936 Opadry OY-28920 38.462 Actual Total1000.0

TABLE 19 48 mg Nanoparticulate Fenofibrate Tablet Formulation Componentg/Kg Fenofibrate 221.05 Hypromellose, USP 44.209 Docusate Sodium, USP4.4082 Sucrose, NF 221.05 Sodium Lauryl Sulfate, NF 15.481 LactoseMonohydrate, NF 201.27 Silicified Microcrystalline Cellulose 131.14Crospovidone, NF 115.12 Magnesium Stearate, NF 1.3843 Opadry OY-2892044.890 Actual Total 1000.0

EXAMPLE 8

The purpose of this example was to compare the dissolution of ananoparticulate 145 mg fenofibrate dosage form according to theinvention with a conventional microcrystalline form of fenofibrate(TRICOR®) in a dissolution medium which is representative of in vivoconditions.

The dissolution of the 145 mg nanoparticulate fenofibrate tablet,prepared in Example 7, was tested in a dissolution medium which isdiscriminating. Such a dissolution medium will produce two verydifferent dissolution curves for two products having very differentdissolution profiles in gastric juices; i.e., the dissolution medium ispredictive of in vivo dissolution of a composition.

The dissolution medium employed was an aqueous medium containing thesurfactant sodium lauryl sulfate at 0.025 M. Determination of the amountdissolved was carried out by spectrophotometry, and the tests wererepeated 12 times. The rotating blade method (European Pharmacopoeia)was used under the following conditions:

volume of media: 1000 ml;

media temperature: 37 ° C.;

blade rotation speed: 75 RPM;

samples taken: every 2.5 minutes;

The results are shown below in Table 20. The table shows the amount (%)of the solid dosage form dissolved at 5, 10, 20, and 30 minutes fortwelve different samples, as well as the mean (%) and standard deviation(%) results. TABLE 20 Dissolution Profile of the NanoparticulateFenofibrate 145 mg Table Test Sample 5 min. 10 min. 20 min. 30 min.  136.1 80.9 101.7 103.6  2 73.4 100.5 100.1 101.8  3 44.0 85.6 100.0 101.4 4 41.0 96.1 102.3 102.5  5 58.7 92.9 103.4 103.5  6 51.9 97.8 102.6103.4  7 28.6 66.9 99.3 100.4  8 44.7 97.4 98.8 99.3  9 30.1 76.9 97.098.0 10 33.6 76.8 101.8 103.5 11 23.5 52.6 95.8 104.0 12 34.6 66.9 102.8102.2 Mean (%) 41.7 82.6 100.5 102.0 Standard Deviation (%) 14.1 15.22.4 1.9

U.S. Pat. No. 6,277,405, for “Fenofibrate Pharmaceutical CompositionHaving High Bioavailability and Method for Preparing It,” describesdissolution of a conventional microcrystalline 160 mg fenofibrate dosageform, e.g. TRICOR®, using the same method described above for thenanoparticulate fenofibrate dosage form (Example 2, cols. 8-9). Theresults show that the conventional fenofibrate dosage form has adissolution profile of 10% in 5 min., 20% in 10 min., 50% in 20 min.,and 75% in 30 min.

The results show that the nanoparticulate fenofibrate dosage form haddramatically more rapid dissolution as compared to the conventionalmicrocrystalline form of fenofibrate. For example, while within 5minutes approximately 41.7% of the nanoparticulate fenofibrate dosageform had dissolved, only 10% of the TRICOR® dosage form had dissolved.Similarly, while at 10 min. about 82.6% of the nanoparticulatefenofibrate dosage form was dissolved, only about 20% of the TRICOR®dosage form had dissolved during the same time period. Finally, while at30 min. basically 100% of the nanoparticulate dosage form had dissolved,only about 75% of the conventional fenofibrate dosage form had dissolvedduring the same time period.

Thus, the nanoparticulate fenofibrate dosage forms of the inventionexhibit dramatically improved rates of dissolution.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the methods and compositionsof the present invention without departing from the spirit or scope ofthe invention. Thus, it is intended that the present invention cover themodifications and variations of this invention provided they come withinthe scope of the appended claims and their equivalents.

1-135. (canceled)
 136. A stable fenofibrate composition for oraladministration comprising particles of fenofibrate having an effectiveaverage particle size of less than about 2000 nm, wherein thecomposition exhibits bioequivalence upon administration to a humansubject in a fed state as compared to administration to a human subjectin a fasted state; where bioequivalency is established by: (a) a 90%Confidence Interval for AUC which is between 80% and 125%, and (b) a 90%Confidence Interval for C_(max), which is between 80% and 125% 137-139.(canceled)
 140. The composition of claim 136, which is bioequivalent toa micronized TRICOR® 54 mg fenofibrate oral solid dosage form.
 141. Thecomposition of claim 136, which is bioequivalent to a micronized TRICOR®160 mg fenofibrate oral solid dosage form.
 142. The composition of claim141, which is a single daily dose.
 143. The composition of claim 136,which is bioequivalent to a micronized TRICOR® 200 mg fenofibrate oralsolid dosage form.
 144. The composition of claim 143, which is a singledaily dose.
 145. The composition of claim 136, wherein the difference inAUC of the fenofibrate composition, when administered to a human subjectin the fed versus the fasted state, is selected from the groupconsisting of less than about 35%, less than about 30%, less than about25%, less than about 20%, less than about 15%, less than about 10%, lessthan about 5%, and less than about 3%.
 146. The composition of claim136, which when administered to a human subject at a dose of about 160mg presents an AUC of about 139 μg/mL.h.
 147. The composition of claim136 which exhibits a T_(max) after administration to fasting humansubjects selected from the group consisting of less than about 6 hours,less than about 5 hours, less than about 4 hours, less than about 3hours, less than about 2 hours, less than about 1 hour, and less thanabout 30 minutes.
 148. The composition of claim 136, wherein incomparative pharmacokinetic testing with a TRICOR® 160 mg tablet orTRICOR® 200 mg capsule, which are standard commercial formulations ofmicrocrystalline fenofibrate, the composition of claim 136 exhibits aT_(max) selected from the group consisting of less than about 90%, lessthan about 80%, less than about 70%, less than about 50%, less thanabout 30%, and less than about 25% of the T_(max) exhibited by theTRICOR® tablet or capsule.
 149. The composition of claim 136, whereinthe fenofibrate is present in an amount selected from the groupconsisting of: (a) about 50 to about 500 g of fenofibrate per kg ofcomposition; (b) about 100 to about 300 g of fenofibrate per kg ofcomposition; (c) about 200 to about 225 g of fenofibrate per kg ofcomposition; and (d) about 119 to about 224 g of fenofibrate per kg ofcomposition.
 150. The composition of claim 136 comprising a dosage ofabout 145 mg of fenofibrate, wherein: (a) the dosage is therapeuticallyeffective; and (b) the composition is bioequivalent to a TRICOR® 160 mgtablet or TRICOR® 200 mg capsule, wherein bioequivalency, whenadministered to a human, is established by a 90% Confidence Interval ofbetween 0.80 and 1.25 for both C_(max) and AUC.
 151. The composition ofclaim 136 comprising a dosage of about 48 mg of fenofibrate, wherein:(a) the dosage is therapeutically effective; and (b) the composition isbioequivalent to a TRICOR® 54 mg tablet, wherein bioequivalency, whenadministered to a human, is established by a 90% Confidence Interval ofbetween 0.80 and 1.25 for both C_(max) and AUC.
 152. The composition ofclaim 136 comprising a dosage of about 160 mg of fenofibrat, whereinfollowing administration to fasting human subjects the blood levels offenofibric acid are at least 4.5 μg/mL at one hour.
 153. The compositionof claim 136, wherein following administration to fasting human subjectsthe blood levels of fenofibric acid are at least 6.5 μg/mL at two hours.154. The composition of claim 136, wherein following administration tofasting human subjects the blood levels of fenofibric acid are at least7.0 μg/mL at three hours.
 155. The composition of claim 136, whereinfollowing administration to fasting human subjects the blood levels offenofibric acid are at least 1.5 μg/mL at twenty-four hours.
 156. Thecomposition of claim 136 comprising a dosage of about 160 mg offenofibrate, wherein following administration to fasting human subjectsthe blood levels of fenofibric acid are at least: (a) 1.0 μg/mL at onehour; (b) 6.5 μg/mL at two hours; (c) 7.0 μg/mL at three hours; and (d)1.5 μg/mL at twenty-four hours.
 157. The composition of claim 136comprising a dosage of about 160 mg of fenofibrate, wherein followingadministration to high fat fed human subjects the blood levels offenofibric acid are at least 4.5 μg/mL at one hour.
 158. The compositionof claim 136, wherein following administration to high fat fed humansubjects the blood levels of fenofibric acid are at least 3.0 μg/mL attwo hours.
 159. The composition of claim 136, wherein followingadministration to high fat fed human subjects the blood levels offenofibric acid are at least 6.0 μg/mL at four hours.
 160. Thecomposition of claim 136, wherein following administration to high fatfed human subjects the blood levels of fenofibric acid are at least 6.5μg/mL at five hours.
 161. The composition of claim 136, whereinfollowing administration to high fat fed human subjects the blood levelsof fenofibric acid are at least 1.5 μg/mL at twenty-four hours.
 162. Thecomposition of claim 136 comprising a dosage of about 160 mg offenofibrate, wherein following administration to high fat fed humansubjects the blood levels of fenofibric acid are at least: (a) 4.5 μg/mLat one hour; (b) 3.0 μg/mL at two hours; (c) 6.0 μg/mL at four hours;(d) 6.5 μg/mL at five hours; and (e) 1.5 μg/mL at twenty-four hours.163. The composition of claim 136, wherein the fenofibrate is selectedfrom the group consisting of a crystalline phase, an amorphous phase, asemi-crystalline phase, a semi-amorphous phase, and mixtures thereof.164. The composition of claim 136, wherein the effective averageparticle size of the particles of fenofibrate is selected from the groupconsisting of less than about 1900 nm, less than about 1800 nm, lessthan about 1700 nm, less than about 1600 nm, less than about 1500 nm,less than about 1400 nm, less than about 1300 nm, less than about 1200nm, less than about 1100 nm, less than about 1000 nm, less than about900 nm, less than about 800 nm, less than about 700 nm, less than about600 nm, less than about 500 nm, less than about 400 nm, less than about300 nm, less than about 250 nm, less than about 200 nm, less than about100 nm, less than about 75 nm, and less than about 50 nm.
 165. Thecomposition of claim 136, wherein the particles of fenofibrate have aparticle size in which the D₉₉ is less than about 500 nm.
 166. Thecomposition of claim 136, wherein the particles of fenofibrate have aparticle size in which the D₅₀ is less than about 350 nm.
 167. Thecomposition of claim 136, wherein the particles of fenofibrate have amean particle size of less than about 100 nm.
 168. The composition ofclaim 136, wherein the composition is formulated for administrationselected from the group consisting of oral, pulmonary, rectal,opthalmic, colonic, parenteral, intracisternal, intravaginal,intraperitoneal, local, buccal, nasal, and topical administration. 169.The composition of claim 136 formulated into a dosage form selected fromthe group consisting of liquid dispersions, oral suspensions, gels,aerosols, ointments, creams, tablets, and capsules.
 170. The compositionof claim 169 formulated into a dosage form selected from the groupconsisting of tablets and capsules.
 171. The composition of claim 170formulated into a tablet.
 172. The composition of claim 136 formulatedinto a dosage form selected from the group consisting of controlledrelease formulations, fast melt formulations, lyophilized formulations,delayed release formulations, extended release formulations, pulsatilerelease formulations, and mixed immediate release and controlled releaseformulations.
 173. The composition of claim 136 further comprising oneor more pharmaceutically acceptable excipients, carriers, or acombination thereof.
 174. The composition of claim 136, wherein withinabout 5 minutes at least about 20% of the composition is dissolved,wherein dissolution is measured in a discriminating aqueous mediacomprising sodium lauryl sulfate at 0.025 M, and wherein the rotatingblade method (European Pharmacopoeia) is used to measure dissolution.175. The composition of claim 136, wherein within about 10 minutes atleast about 40% of the composition is dissolved, wherein dissolution ismeasured in a discriminating aqueous media comprising sodium laurylsulfate at 0.025 M, and wherein the rotating blade method (EuropeanPharmacopoeia) is used to measure dissolution.
 176. The composition ofclaim 136, wherein within about 20 minutes at least about 70% of thecomposition is dissolved, wherein dissolution is measured in adiscriminating aqueous media comprising sodium lauryl sulfate at 0.025M, and wherein the rotating blade method (European Pharmacopoeia) isused to measure dissolution.
 177. The composition of claim 136, wherein:(a) within about 5 minutes at least about 30% of the composition isdissolved; (b) within about 10 minutes at least about 70% of thecomposition is dissolved; and (c) within about 20 minutes at least about90% of the composition is dissolved, wherein dissolution is measured ina discriminating aqueous media comprising sodium lauryl sulfate at 0.025M, and wherein the rotating blade method (European Pharmacopoeia) isused to measure dissolution.
 178. The composition of claim 136, wherein:(a) within about 5 minutes at least about 40% of the composition isdissolved; (b) within about 10 minutes at least about 80% of thecomposition is dissolved; and (c) within about 20 minutes at least about100% of the composition is dissolved, wherein dissolution is measured ina discriminating aqueous media comprising sodium lauryl sulfate at 0.025M, and wherein the rotating blade method (European Pharmacopoeia) isused to measure dissolution.
 179. The composition of claim 136 whereinupon administration the composition redisperses such that theredispersed particles of fenofibrate or a salt thereof have an effectiveaverage particle size of less than about 2000 nm.
 180. The compositionof claim 179, wherein the redispersed particles of fenofibrate or a saltthereof have an effective average particle size selected from the groupconsisting of less than about 1900 nm, less than about 1800 nm, lessthan about 1700 nm, less than about 1600 nm, less than about 1500 nm,less than about 1400 nm, less than about 1300 nm, less than about 1200nm, less than about 1100 nm, less than about 1000 nm, less than about900 nm, less than about 800 nm, less than about 700 nm, and less thanabout 600 nm.
 181. The composition of claim 136, wherein the compositionredisperses in a biorelevant media such that the redispersed particlesof fenofibrate or a salt thereof have an effective average particle sizeof less than about 2000 nm.
 182. The composition of claim 181, whereinthe redispersed particles of fenofibrate or a salt thereof have aneffective average particle size selected from the group consisting ofless than about 1900 nm, less than about 1800 nm, less than about 1700nm, less than about 1600 nm, less than about 1500 nm, less than about1400 nm, less than about 1300 nm, less than about 1200 nm, less thanabout 1100 nm, less than about 1000 nm, less than about 900 nm, lessthan about 800 nm, less than about 700 nm, less than about 600 nm. 183.The composition of claim 136, additionally comprising one or more activeagents selected from the group consisting of HMG CoA reductaseinhibitors and antihypertensives.
 184. The composition of claim 136,wherein within about 5 minutes at least about 30% of the composition isdissolved, wherein dissolution is measured in a discriminating aqueousmedia comprising sodium lauryl sulfate at 0.025 M, and wherein therotating blade method (European Pharmacopoeia) is used to measuredissolution.
 185. The composition of claim 136, wherein within about 5minutes at least about 40% of the composition is dissolved, whereindissolution is measured in a discriminating aqueous media comprisingsodium lauryl sulfate at 0.025 M, and wherein the rotating blade method(European Pharmacopoeia) is used to measure dissolution.
 186. Thecomposition of claim 136, wherein within about 10 minutes at least about50% of the composition is dissolved, wherein dissolution is measured ina discriminating aqueous media comprising sodium lauryl sulfate at 0.025M, and wherein the rotating blade method (European Pharmacopoeia) isused to measure dissolution.
 187. The composition of claim 136, whereinwithin about 10 minutes at least about 60% of the composition isdissolved, wherein dissolution is measured in a discriminating aqueousmedia comprising sodium lauryl sulfate at 0.025 M, and wherein therotating blade method (European Pharmacopoeia) is used to measuredissolution.
 188. The composition of claim 136, wherein within about 10minutes at least about 70% of the composition is dissolved, whereindissolution is measured in a discriminating aqueous media comprisingsodium lauryl sulfate at 0.025 M, and wherein the rotating blade method(European Pharmacopoeia) is used to measure dissolution.
 189. Thecomposition of claim 136, wherein within about 10 minutes at least about80% of the composition is dissolved, wherein dissolution is measured ina discriminating aqueous media comprising sodium lauryl sulfate at 0.025M, and wherein the rotating blade method (European Pharmacopoeia) isused to measure dissolution.
 190. The composition of claim 136, whereinwithin about 20 minutes at least about 80% of the composition isdissolved, wherein dissolution is measured in a discriminating aqueousmedia comprising sodium lauryl sulfate at 0.025 M, and wherein therotating blade method (European Pharmacopoeia) is used to measuredissolution.
 191. The composition of claim 136, wherein within about 20minutes at least about 90% of the composition is dissolved, whereindissolution is measured in a discriminating aqueous media comprisingsodium lauryl sulfate at 0.025 M, and wherein the rotating blade method(European Pharmacopoeia) is used to measure dissolution.
 192. Thecomposition of claim 136, wherein within about 20 minutes at least about100% of the composition is dissolved, wherein dissolution is measured ina discriminating aqueous media comprising sodium lauryl sulfate at 0.025M, and wherein the rotating blade method (European Pharmacopoeia) isused to measure dissolution.
 193. The composition of claim 180, whereinthe redispersed particles of fenofibrate or a salt thereof have aneffective average particle size selected from the group consisting ofless than about 500 nm, less than about 400 nm, less than about 300 nm,less than about 250 nm, less than about 200 nm, less than about 150 nm,less than about 100 nm, less than about 75 nm, and less than about 50 nm194. The composition of claim 182, wherein the redispersed particles offenofibrate or a salt thereof have an effective average particle sizeselected from the group consisting of less than about 500 nm, less thanabout 400 nm, less than about 300 nm, less than about 250 nm, less thanabout 200 nm, less than about 150 nm, less than about 100 nm, less thanabout 75 nm, and less than about 50 nm
 195. A stable fenofibratecomposition for oral administration comprising particles of fenofibratehaving an effective average particle size of less than about 2000 nm ina dosage form for oral administration which is a tablet or capsule ofabout 145 mg of fenofibrate, wherein the composition exhibitsbioequivalence upon administration to a human subject in a fed state ascompared to administration to a human subject in a fasted state; wherebioequivalency is established by: (a) a 90% Confidence Interval for AUCwhich is between 80% and 125%, and (b) a 90% Confidence Interval forC_(max), which is between 80% and 125%.